This investigation will be a randomized, observer-masked, controlled, split-body, human-subjects clinical trial. Of note, we will be using standard-of-care local anesthetics under their FDA approved purpose and do not plan to research a possible change of indication or use of these drugs as part of this research project.
Enrollment. Subjects will be volunteers of both sexes, age 18 and older. Volunteers will be solicited using newspaper advertisements, fliers, the CTRI Research Match, and an existing database of volunteers (IRB approved). If a volunteer meets inclusion/exclusion criteria and desires study participation, written, informed consent will be obtained. Selection for inclusion will not be based on race or socioeconomic status. The study population of interest includes men and women of all races and socioeconomic status. A urine pregnancy test will be administered to all women of childbearing age following written informed consent but before any study interventions. This urine test will be administered by CTRI nursing staff using standard, FDA-approved urine pregnancy testing devices.
Inclusion and Exclusion Criteria. See section #10 below.
Perineural catheter insertion. Following written, informed consent, subjects will be admitted to the UCSD CTRI Center for Clinical Research Services (CCR) inpatient unit and have demographic/morphometric data recorded (e.g., age, weight, height). An intravenous line will be placed in an upper extremity, followed by external monitors (pulse oximeter, blood pressure, and EKG), and oxygen by nasal cannula. Sedation will be provided with intravenous fentanyl (50 μg) and/or midazolam (1 mg), or oral valium (10 mg) and/or dilaudid (4 mg), as necessary. Subjects will then have bilateral adductor canal perineural catheters placed using standard UC San Diego techniques.
Treatment Group Assignment. Subjects will act as their own controls: The dominant side (left or right) will be randomized to one of two treatment groups: ropivacaine 0.2% administration as either a basal infusion (8 mL/h) or bolus doses (8 mL administered hourly). The non-dominant contralateral side will receive the other possible treatment. Randomization will be based on computer-generated codes. Randomization will be in blocks of two, and stratified by sex. An infusion pump with study infusate will be attached to each of the perineural catheters and initiated at Hour 0. The basal rate and bolus volume will depend upon the treatment group (note that the basal rate and bolus volume differ for each treatment group, but the total dose of local anesthetic is the same for each):
Treatment Group Basal Rate (mL/h) Basal Dose (mg/h) Bolus Volume (mL) Bolus Dose (mg) Total Dose (mg/h) Basal Infusion 8 16 0 0 16 Bolus Doses 0 0 8 16 16
The tubing from the pumps to the subjects will be gently wound at least 5 rotations and covered with opaque tape, masking which perineural catheter is receiving which treatment (ropivacaine is clear, so the flow through the clear tubing from the tape to the perineural catheters will not be visually distinguishable).
Local Anesthetic Administration. The infusion pump administering the basal infusion will be initiated at Hour 0. The infusion pump administering bolus doses will administer a 8 mL bolus dose each hour beginning at Hour 0. Perineural catheters will be removed after 8 hours.
To check the perineural catheter placement accuracy, the adductor canal nerve block will be evaluated 8 hours after local anesthetic initiation and considered successful when subjects experience a decreased sensation to cold of the skin in the saphenous nerve distribution as compared with their ipsilateral upper extremity. Subjects will be deemed non-responders if both extremities failed to exhibit any increase in tolerance to cutaneous electrical current by Hour 8. For unsuccessful perineural catheter insertion, non-responders, or if a perineural catheter is inadvertently dislodged prior to the measurement of the primary endpoint, the data will not be included in the analyses and the subject dropped from the study.
Food and Drink: Both food and accompanying beverages/water will be provided by the hospital and served by the nursing staff immediately following catheter insertion. Meals will be provided without charge to the study subjects. There is no restriction on oral intake following catheter insertion. Subjects will remain within the CTRI-CCR until the following morning for the final measurement.
Outcome Measurements. We have selected measures that have established reliability and validity. Staff blinded to treatment group assignment will perform all measures and assessments. Measurements will be performed prior to local anesthetic administration initiation ("baseline"; Hour 0); as well as hourly following local anesthetic infusion/bolus initiation through Hour 14 (and one final measurement set prior to discharge the following morning at approximately Hour 22; see Table below). For all measurements, the dominant side will always be tested first, followed by the contralateral side.
Tolerance of transcutaneous electrical stimulation: Evaluated in the seated position using transcutaneous electrical stimulation (TES) in the same manner as described throughout the anesthesia literature (this is a "gold standard" for regional anesthesia studies). EKG pads will be positioned over the proximal patella and quadriceps tendon 1 cm medial of midline and attached to a nerve stimulator. The current will be increased from 0 mA until the subject reports slight discomfort (or, up to a maximum of 80 mA), at which time the current is recorded as the TES value and the nerve stimulator turned off.
Quadriceps femoris muscle strength: Evaluated using a portable isometric force dynamometer to measure the maximum voluntary isometric contraction (MVIC) in a seated position. The primary end point will be the quadriceps femoris maximum voluntary isometric contraction (MVIC) expressed as a percentage of the pre-ropivacaine (baseline) MVIC: post / pre x 100; with the two sides of each subject compared with each other at Hour 8.
Statistical Analysis Plan. We will assess the noninferiority of the bolus method (hourly 8 mL ropivacaine 0.2% bolus doses) compared to basal infusion (ropivacaine 0.2% 8 mL/h continuous basal infusion) on the primary endpoint of tolerance to cutaneous current at 8 hours using a 1-tailed t-test at the 0.025 significance level with an a priori-specified noninferiority delta of 10 mA. A value of 10 mA is determined a priori to be the smallest difference that would be clinically important between groups. This value is considered the minimally clinically-relevant current since it approximates the tolerated electrical current range at baseline of the general population-in other words, natural variability and therefore a relatively small amount of current to detect. A positive test for noninferiority will be accompanied by the 95% confidence interval (0.025 in the hypothesized direction) for the difference in means not including the noninferiority delta.
Secondary analysis will assess noninferiority of the bolus to the basal infusion method on mean tolerance to cutaneous current across all time points measured, using a noninferiority delta of 10 mA as above. In this repeated measures setting, noninferiority will be assessed in the context of a linear mixed model adjusting for the within-subject correlation (using an auto-regressive correlation structure). If the time-by-group interaction is non-significant (P\>0.20) we will assess noninferiority collapsing over time and constructing a 1-tailed t-test (using noninferiority delta of 10 mA) based on the model-based treatment effect for bolus versus basal infusion. In presence of a group-time interaction noninferiority will be assessed separately at each time point and a Holm-Bonferroni correction made for multiple comparisons to maintain the hypothesis-wise type I error at 0.025.
We will also assess noninferiority of bolus to basal infusion on the secondary endpoint of quadriceps femoris MVIC (22 hours total) using a mixed effects model as described above.
The rejection region for a noninferiority test includes superiority, by definition (i.e., "not worse" implies either equivalent or better). Therefore, if bolus is found to not only be noninferior, but also superior, we will be able to claim superiority. This will be evidenced by the 95% CI for the difference between means falling above zero.
Although we hypothesize that the bolus method will be noninferior to basal infusion, it is possible that basal infusion would be noninferior to bolus. Therefore, we will also conduct the above tests assessing noninferiority of basal infusion to bolus. If noninferiority is found in both directions, we will claim equivalence at ±10mA. SAS software 9.3 (SAS Institute, Cary, NC, USA) and R software versions 2.15.3 (The R Foundation for Statistical Computing, Vienna, Austria) will be used for all analyses.
Sample Size Estimation. Sample size calculations are based on the primary aim of determining the relationship between perineural ropivacaine delivery technique (basal vs. bolus) and continuous adductor canal nerve block effects. To this end, we will perform a noninferiority trial with the primary endpoint designated as the maximum tolerance to transcutaneous electrical stimulation at Hour 8. With 24 subjects we will have approximately 90% power (88%) at the 0.025 significance level to detect noninferiority of bolus ropivacaine to basal infusion ropivacaine on mean tolerance to transcutaneous electrical stimulation at Hour 8 using an a priori noninferiority delta of 10 mA. Based on previously-published data, this conservatively assumes a standard deviation of tolerance difference between legs of 15 mA.
We will apply the same analysis of percent change from baseline at Hour 0 to the secondary outcome measures. We will also examine the time profiles of the responses over time with spaghetti and mean plots. Further secondary analyses will include mixed-effects modeling of the repeated hourly measures to confirm the analysis of percent change at 8 hours. These models will account for the hierarchical correlation of paired measures from each subject over time. We will use these models to test the effects of subject characteristics, including handedness, sex, height, weight, body mass index, and age.
