Intravenous Dexmedetomidine, Dexamethasone and Interscalene Block Duration After Arthroscopic Shoulder Surgery

Study Overview
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Brief Summary
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In this single-centre, double-blinded, randomized controlled superiority trial, 189 participants having outpatient, arthroscopic shoulder surgery will be randomized into 3 equal sized groups. All participants will receive a standardized interscalene brachial plexus block and 4mg of dexamethasone or 50mcg of dexmedetomidine or both intravenously just prior to their surgery. The purpose of this study is to provide a head to head comparison of two types intravenous adjuncts to ISB, corticosteroids and alpha 2 agonists, and determine if their combination, or either one alone provides superior postoperative analgesia in arthroscopic shoulder surgery patients, as well as possibly show a synergistic relationship between the two adjuncts. The investigators hypothesize the combination of adjuncts will provide a longer duration of analgesia compared to either single agent.

Detailed Description
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BACKGROUND & RATIONALE Optimal postoperative analgesia is very important in the ambulatory arthroscopic shoulder surgery patient population; interscalene blocks are used for this surgery because they reduce acute pain and have opioid sparing effects postoperatively. While older patients, higher ASA grades and more complex arthroscopic procedures are risk factors for unplanned overnight admissions, in the ambulatory surgery setting, poor analgesia is one of the most common reasons a patient visits a health care provider after their surgery. Approximately 30 % of patients undergoing arthroscopic surgery globally experience significant postoperative pain within the first 24 hours post surgery. In light of this, interscalene brachial plexus blockade (ISB) has been found to be the most effective and preferred method of analgesia for arthroscopic shoulder surgeries when compared to subacromial/intra-articular injections, cryotherapy and oral pain medications. ISB usually consists of a single injection of local anesthetic, anywhere from 5 to 30 minutes prior to shoulder surgery. Although ISB reduces postoperative pain in arthroscopic shoulder surgeries, the length of analgesia from a single injection of local anesthetic is limited to 6 to 15 hours after surgery. Due to the limited duration of analgesia, interscalene catheters have been studied for prolongation of analgesia via continuous infusion of local anesthetics. Although continuous catheter infusions are effective and feasible, there exist several complications such as dyspnea, peripheral neuropathies, nausea, and practical challenges that limit their wider application in an ambulatory setting. Recently, different adjuncts given in combination with local anesthetics have been used to prolong the analgesic duration of a single injection ISB. These adjuncts have been given by both the intravenous and by the perineural routes, where perineural means the adjunct is injected with the local anesthetic around the brachial plexus. Dexamethasone, a potent glucocorticoid, has been shown in multiple studies to prolong the duration of analgesia of the ISB compared to placebo when administered either perineurally or intravenously. A recently completed large trial (in press) at our centre showed that the duration of analgesia (mean (standard deviation), in hours (h)) with 4mg of intravenous dexamethasone (24.0 (4.6)h) is not significantly different from 8mg (24.8 (6.4)h) and only slightly shorter than perineural dexamethasone doses of 4mg (25.4 (6.6)h) or 8mg (27.2 (8.5)h). The 4mg intravenous dose was favored given the established safety of the intravenous route, its approximately equivalent effectiveness compared to the higher 8mg dose and the absence of differences in adverse effects between groups. Dexmedetomidine, a highly selective α2 adrenergic agonist with sedative and analgesic properties, has also been shown to potentiate peripheral nerve blockade and prolong the duration of analgesia versus placebo when used as an adjunct to local anesthetic for regional anesthesia, including interscalene block. Most studies have compared perineural dexmedetomidine to placebo, as is the case for other adjuncts such as dexamethasone, even though there is less experience with the perineural route for dexmedetomidine compared to dexamethasone. Interestingly, a recent study found both intravenous and perineural dexmedetomidine reduced the 24 hour opioid consumption and comparably prolonged the duration of ISB analgesia compared to placebo. In a recent meta-analysis, a 50-60ug Dexmedetomidine perineural or intravenous dose maximized sensory block duration while minimizing hemodynamic side effects. To our knowledge, there are no published studies comparing the analgesic duration of ISB between dexamethasone and dexmedetomidine, and no studies have evaluated whether there is additional benefit to administering these widely available medications in combination. Three ongoing studies are comparing dexamethasone and dexmedetomidine as single adjuncts, without a combination. All three of these studies are using the perineural route, despite the established safety and effectiveness of the intravenous route for both drugs. With this study we are seeking to improve our patients' postoperative experience with superior analgesia by better defining the relative analgesic effectiveness of dexamethasone and dexmedetomidine when given alone or in combination as intravenous adjuncts to ISB. OBJECTIVES AND HYPOTHESES In outpatients undergoing arthroscopic shoulder surgery with Interscalene Block: I. To determine if there is a significant increase in duration of analgesia when combining intravenous dexamethasone and dexmedetomidine compared to administering each adjunct individually. We hypothesize the combination of adjuncts will provide a longer duration of analgesia compared to either single agent. II. To compare the effect of Dexamethasone to Dexmedetomidine on duration of analgesia when given individually. We hypothesize that there will be no significant difference between the two adjuncts. METHODS This single-centre, double-blinded, randomized controlled superiority trial has three parallel groups and 1:1:1 randomization. Consenting and eligible adult ambulatory patients undergoing arthroscopic shoulder surgery will receive preoperative, ultrasound guided ISB with 30 millilitres (mL) of 0.5% bupivacaine and 4mg of preservative free dexamethasone or 50mcg of dexmedetomidine or both intravenously. The remainder of the intraoperative and postoperative care is at the discretion of the attending anesthesiologist and surgeon. The primary outcome is analgesic block duration. The power analysis for this study was based on published results from previous studies, as well as our recent work. With a two-tailed alpha error of 0.05, and a standard deviation of 5.0 hours in each group, 180 total patients would provide greater than 90% power to detect a difference of 3.0 hours in block duration. To account for a 5% attrition rate we propose recruiting 63 patients per group (189 patient's total). Outcomes will be assessed by chart review and telephone follow up on postoperative day one, postoperative day 2 (if necessary), and postoperative day 14. After collecting 102 primary outcomes, we will compare the primary outcome between the combination and each of the single adjuncts. At this point the study will be 90% powered to detect a difference of 6.0h in block duration, even if the standard deviations are higher than expected, at 7.5 hours. If the combination is superior to both of the single agents, the study will be terminated. The principle investigator cancelled this interim analysis on 18 December 2017 after consultation with the study statistician and research team. After reconsidering the original power calculations, the clinically plausible differences between groups, and the high level of statistical significance recommended for interim analyses, it was determined that this interim analysis would be very unlikely to convincingly demonstrate the superiority of the combination over the single agents. As of 18 December 2017 90 patients have participated in the study and recruitment is on schedule. The entire research team has been and will continue to be blinded to outcome data by group assignment until all 189 patients have participated, which is expected to occur in the second quarter of 2018. The primary outcome analysis will analyze by intention to treat only those patients who were randomized and did receive an attempt at an interscalene block. A secondary analysis will exclude patients who had a failed interscalene block in the post anesthesia care unit. A tertiary analysis will be a multivariable analysis adjusted for demographics, preoperative naproxen use, use of general anesthesia, cumulative analgesic use and failed interscalene block.

Official Title
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Analgesic Duration of Interscalene Block After Outpatient Arthroscopic Shoulder Surgery With Intravenous Dexamethasone, Dexmedetomidine or Their Combination: A Randomized Controlled Trial

Conditions
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Pain, Postoperative, Shoulder Joint Disorder, Ambulatory Surgical Procedures, Brachial Plexus Block

Intervention / Treatment
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* Drug: Dexamethasone
* Drug: Dexmedetomidine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Elective ambulatory surgery patients undergoing arthroscopic shoulder surgery Including rotator cuff repair Stabilization procedures Acromioplasty Debridement and distal clavicle excision Exclusion Criteria: Patient refusal Diabetes Pregnancy Coagulopathy significant enough to be a contraindication to regional anesthesia as determined by the attending anesthesiologist Sensitivity to local anesthetics, dexamethasone or dexmedetomidine Severe chronic obstructive pulmonary disease Contralateral vocal cord paralysis Contralateral diaphragmatic paralysis Surgical limb brachial plexus neuropathy Interscalene block site infection Systemic glucocorticoids in the last 2 weeks Epidural or intraarticular steroid injection in the past 3 months Chronic opioid use defined as daily use for the last two weeks Active peptic ulcer disease End-stage renal disease Cirrhotic liver disease Ventricular dysfunction Advanced heart block Previous participation in the study.

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: Dexamethasone<br>4 milligrams dexamethasone administered once intravenously with a 30 millilitres 0.5% bupivacaine interscalene brachial plexus block | Drug: Dexamethasone<br>* 0.4 millilitres (mL) of 10 milligram per mL sterile, preservative free solution diluted in 50 or 100mL of normal saline and administered once, over approximately 15 minutes, in the immediate preoperative period.<br>* Other names: Dexamethasone Sodium Phosphate USP (1 millilitre vial);|
| Active Comparator: Dexmedetomidine<br>50 micrograms dexmedetomidine administered once intravenously with a 30 millilitres 0.5% bupivacaine interscalene brachial plexus block | Drug: Dexmedetomidine<br>* 0.5 millilitres (mL) of 100 microgram per mL sterile, preservative free solution diluted in 50 or 100mL of normal saline and administered once, over approximately 15 minutes, in the immediate preoperative period.<br>* Other names: Dexmedetomidine Hydrochloride for Injection;|
| Active Comparator: Dexamethasone and Dexmedetomidine<br>4 milligrams dexamethasone and 50 micrograms dexmedetomidine administered once intravenously with a 30 millilitres 0.5% bupivacaine interscalene brachial plexus block | Drug: Dexamethasone<br>* 0.4 millilitres (mL) of 10 milligram per mL sterile, preservative free solution diluted in 50 or 100mL of normal saline and administered once, over approximately 15 minutes, in the immediate preoperative period.<br>* Other names: Dexamethasone Sodium Phosphate USP (1 millilitre vial);Drug: Dexmedetomidine<br>* 0.5 millilitres (mL) of 100 microgram per mL sterile, preservative free solution diluted in 50 or 100mL of normal saline and administered once, over approximately 15 minutes, in the immediate preoperative period.<br>* Other names: Dexmedetomidine Hydrochloride for Injection;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of analgesia after ISB | Time from block performance to the first time shoulder pain was experienced after the surgery, rounded to the nearest 0.1 hours, as reported by the participant at telephone follow-up on postoperative day one, or if necessary, postoperative day 2. | Time-to-event outcome measure, assessed up to the end of postoperative day 3 (approximately 84 hours from performance of the block | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Block Success or Failure | The block will be considered failed if the patient required opioid analgesia for surgical site pain during their stay in the post anesthesia care unit, as determined by the patient's nurse. At our facility, patients are discharged home directly from the post anesthesia care unit. | Assessed at discharge from the post anesthesia care unit, an expected average of 5 hours after the performance of the block. | 
| Cumulative Analgesic Consumption in the post anesthesia care unit | Measured as equivalent milligrams of morphine | Change outcome measure: From admission to the post anesthesia care unit (an expected average of 2.5 hours after performance of the block), to discharge from the post anesthesia care unit (an expected average of 4 hours after performance of the block) | 
| Cumulative Analgesic Consumption from post anesthesia care unit discharge until the time the primary outcome occurred | Measured as equivalent milligrams of morphine | Change outcome measure: From discharge from the post anesthesia care unit (an expected average of 5 hours after performance of the block), to the occurrence of the primary outcome (an expected average of 28 hours after performance of the block) | 
| Unplanned Postoperative Hospital Admission, as reported at telephone follow up or chart review | Transfer or admission to hospital during the postoperative period between admission to the post anesthesia care unit and telephone follow up on postoperative day one | Assessed at telephone follow up on postoperative day one and chart review | 
| New Persistent Neurologic Symptoms | Patient will be asked whether they are experiencing any tingling, numbness or weakness in the surgical limb, or hoarseness or dyspnea. Patients answering yes to any of the above will have a detailed telephone assessment and be reassessed by telephone at 6 months postoperatively | Assessed at postoperative day 14 | 
| Post anesthesia care unit length of stay in minutes | Amount of time between admission and discharge from the post anesthesia care unit. | Assessed at discharge from the post anesthesia care unit, an expected average of 4 hours after performance of the block. | 
| The QoR-15 questionnaire | A standardized and validated 15 item questionnaire consisting exclusively of 11 point integer scale questions (10 = all the time, 0 = none of the time) designed to assess quality of recovery, physical and mental wellbeing in patients recovering from surgery. A total composite score is measured as the total of all 15 individual scores. | Assessed at postoperative day one. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Shoulder Joint, Arthroscopy, Ambulatory surgical procedures, Pain, Postoperative, Brachial Plexus Block, Corticosteroid, Dexamethasone, Dexmedetomidine, Bupivacaine, Alpha 2 agonist, Postoperative analgesia