<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT02219438</url>
  </required_header>
  <id_info>
    <org_study_id>Adductor Canal Basal vs Bolus</org_study_id>
    <nct_id>NCT02219438</nct_id>
  </id_info>
  <brief_title>Continuous Adductor Canal Nerve Blocks: Relative Effects of a Basal Infusion v. Hourly Bolus Doses</brief_title>
  <official_title>Continuous Adductor Canal Nerve Blocks: Relative Effects of a Basal Infusion v. Hourly Bolus Doses</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of California, San Diego</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of California, San Diego</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Patients usually experience moderate-to-severe pain following the knee replacement that is&#xD;
      often treated with a femoral nerve block (injection of numbing medicine placed around the&#xD;
      main nerve of the knee joint). To make the nerve block last longer, a tiny tube is often&#xD;
      placed next to the nerve and numbing medicine is infused for multiple days. However, while&#xD;
      the numbing medicine takes away pain, it also decreases sensations, muscle strength, and&#xD;
      proprioception (knowing where the leg is in space without looking at it) which greatly&#xD;
      increases the risk of falling. Since falling can be catastrophic following major surgery, a&#xD;
      femoral nerve blocks are being phased out by surgeons and anesthesiologists. The&#xD;
      most-promising replacement is called an adductor canal nerve block. For this new type of&#xD;
      block, a perineural catheter is inserted into a small canal in the middle of the upper leg.&#xD;
      This canal contains the sensory nerve fibers leading to the knee, and only a single nerve&#xD;
      that serves a relatively small muscle. Multiple studies have demonstrated a dramatic increase&#xD;
      in muscle strength using the new adductor canal block compared with the traditional femoral&#xD;
      block. However, practitioners perceptions of the new block is that it provides insufficient&#xD;
      pain control following knee arthroplasty, even though all of the sensory nerves affected with&#xD;
      the femoral block are also-theoretically-affected with the adductor canal block. One reason&#xD;
      for this difference may be the small canal of the latter which is a relatively tight area in&#xD;
      which the numbing medicine might not spread particularly well (due to pressure from&#xD;
      surrounding tissues). One way to possibly counter this issue is by providing repeated boluses&#xD;
      of the numbing medicine that will improve the medicine's spread relative to a&#xD;
      more-traditional slow, continuous (&quot;basal&quot;) infusion. This study seeks to compare these two&#xD;
      techniques of medication administration through perineural adductor canal catheters:&#xD;
&#xD;
      Our primary aim is to test the hypothesis that, for continuous adductor canal blocks,&#xD;
      providing local anesthetic as repeated, hourly bolus doses results in an increased sensory&#xD;
      block compared with providing local anesthetic as a continuous basal infusion at an&#xD;
      equivalent hourly dose.&#xD;
&#xD;
      As a secondary aim, we hypothesize that, for continuous adductor canal blocks, providing&#xD;
      local anesthetic as repeated, hourly bolus doses results in either equivalent or less motor&#xD;
      block compared with providing local anesthetic as a continuous basal infusion at an&#xD;
      equivalent hourly dose.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This investigation will be a randomized, observer-masked, controlled, split-body,&#xD;
      human-subjects clinical trial. Of note, we will be using standard-of-care local anesthetics&#xD;
      under their FDA approved purpose and do not plan to research a possible change of indication&#xD;
      or use of these drugs as part of this research project.&#xD;
&#xD;
      Enrollment. Subjects will be volunteers of both sexes, age 18 and older. Volunteers will be&#xD;
      solicited using newspaper advertisements, fliers, the CTRI Research Match, and an existing&#xD;
      database of volunteers (IRB approved). If a volunteer meets inclusion/exclusion criteria and&#xD;
      desires study participation, written, informed consent will be obtained. Selection for&#xD;
      inclusion will not be based on race or socioeconomic status. The study population of interest&#xD;
      includes men and women of all races and socioeconomic status. A urine pregnancy test will be&#xD;
      administered to all women of childbearing age following written informed consent but before&#xD;
      any study interventions. This urine test will be administered by CTRI nursing staff using&#xD;
      standard, FDA-approved urine pregnancy testing devices.&#xD;
&#xD;
      Inclusion and Exclusion Criteria. See section #10 below.&#xD;
&#xD;
      Perineural catheter insertion. Following written, informed consent, subjects will be admitted&#xD;
      to the UCSD CTRI Center for Clinical Research Services (CCR) inpatient unit and have&#xD;
      demographic/morphometric data recorded (e.g., age, weight, height). An intravenous line will&#xD;
      be placed in an upper extremity, followed by external monitors (pulse oximeter, blood&#xD;
      pressure, and EKG), and oxygen by nasal cannula. Sedation will be provided with intravenous&#xD;
      fentanyl (50 μg) and/or midazolam (1 mg), or oral valium (10 mg) and/or dilaudid (4 mg), as&#xD;
      necessary. Subjects will then have bilateral adductor canal perineural catheters placed using&#xD;
      standard UC San Diego techniques.&#xD;
&#xD;
      Treatment Group Assignment. Subjects will act as their own controls: The dominant side (left&#xD;
      or right) will be randomized to one of two treatment groups: ropivacaine 0.2% administration&#xD;
      as either a basal infusion (8 mL/h) or bolus doses (8 mL administered hourly). The&#xD;
      non-dominant contralateral side will receive the other possible treatment. Randomization will&#xD;
      be based on computer-generated codes. Randomization will be in blocks of two, and stratified&#xD;
      by sex. An infusion pump with study infusate will be attached to each of the perineural&#xD;
      catheters and initiated at Hour 0. The basal rate and bolus volume will depend upon the&#xD;
      treatment group (note that the basal rate and bolus volume differ for each treatment group,&#xD;
      but the total dose of local anesthetic is the same for each):&#xD;
&#xD;
      Treatment Group Basal Rate (mL/h) Basal Dose (mg/h) Bolus Volume (mL) Bolus Dose (mg) Total&#xD;
      Dose (mg/h) Basal Infusion 8 16 0 0 16 Bolus Doses 0 0 8 16 16&#xD;
&#xD;
      The tubing from the pumps to the subjects will be gently wound at least 5 rotations and&#xD;
      covered with opaque tape, masking which perineural catheter is receiving which treatment&#xD;
      (ropivacaine is clear, so the flow through the clear tubing from the tape to the perineural&#xD;
      catheters will not be visually distinguishable).&#xD;
&#xD;
      Local Anesthetic Administration. The infusion pump administering the basal infusion will be&#xD;
      initiated at Hour 0. The infusion pump administering bolus doses will administer a 8 mL bolus&#xD;
      dose each hour beginning at Hour 0. Perineural catheters will be removed after 8 hours.&#xD;
&#xD;
      To check the perineural catheter placement accuracy, the adductor canal nerve block will be&#xD;
      evaluated 8 hours after local anesthetic initiation and considered successful when subjects&#xD;
      experience a decreased sensation to cold of the skin in the saphenous nerve distribution as&#xD;
      compared with their ipsilateral upper extremity. Subjects will be deemed non-responders if&#xD;
      both extremities failed to exhibit any increase in tolerance to cutaneous electrical current&#xD;
      by Hour 8. For unsuccessful perineural catheter insertion, non-responders, or if a perineural&#xD;
      catheter is inadvertently dislodged prior to the measurement of the primary endpoint, the&#xD;
      data will not be included in the analyses and the subject dropped from the study.&#xD;
&#xD;
      Food and Drink: Both food and accompanying beverages/water will be provided by the hospital&#xD;
      and served by the nursing staff immediately following catheter insertion. Meals will be&#xD;
      provided without charge to the study subjects. There is no restriction on oral intake&#xD;
      following catheter insertion. Subjects will remain within the CTRI-CCR until the following&#xD;
      morning for the final measurement.&#xD;
&#xD;
      Outcome Measurements. We have selected measures that have established reliability and&#xD;
      validity. Staff blinded to treatment group assignment will perform all measures and&#xD;
      assessments. Measurements will be performed prior to local anesthetic administration&#xD;
      initiation (&quot;baseline&quot;; Hour 0); as well as hourly following local anesthetic infusion/bolus&#xD;
      initiation through Hour 14 (and one final measurement set prior to discharge the following&#xD;
      morning at approximately Hour 22; see Table below). For all measurements, the dominant side&#xD;
      will always be tested first, followed by the contralateral side.&#xD;
&#xD;
      Tolerance of transcutaneous electrical stimulation: Evaluated in the seated position using&#xD;
      transcutaneous electrical stimulation (TES) in the same manner as described throughout the&#xD;
      anesthesia literature (this is a &quot;gold standard&quot; for regional anesthesia studies). EKG pads&#xD;
      will be positioned over the proximal patella and quadriceps tendon 1 cm medial of midline and&#xD;
      attached to a nerve stimulator. The current will be increased from 0 mA until the subject&#xD;
      reports slight discomfort (or, up to a maximum of 80 mA), at which time the current is&#xD;
      recorded as the TES value and the nerve stimulator turned off.&#xD;
&#xD;
      Quadriceps femoris muscle strength: Evaluated using a portable isometric force dynamometer to&#xD;
      measure the maximum voluntary isometric contraction (MVIC) in a seated position. The primary&#xD;
      end point will be the quadriceps femoris maximum voluntary isometric contraction (MVIC)&#xD;
      expressed as a percentage of the pre-ropivacaine (baseline) MVIC: post / pre x 100; with the&#xD;
      two sides of each subject compared with each other at Hour 8.&#xD;
&#xD;
      Statistical Analysis Plan. We will assess the noninferiority of the bolus method (hourly 8 mL&#xD;
      ropivacaine 0.2% bolus doses) compared to basal infusion (ropivacaine 0.2% 8 mL/h continuous&#xD;
      basal infusion) on the primary endpoint of tolerance to cutaneous current at 8 hours using a&#xD;
      1-tailed t-test at the 0.025 significance level with an a priori-specified noninferiority&#xD;
      delta of 10 mA. A value of 10 mA is determined a priori to be the smallest difference that&#xD;
      would be clinically important between groups. This value is considered the minimally&#xD;
      clinically-relevant current since it approximates the tolerated electrical current range at&#xD;
      baseline of the general population-in other words, natural variability and therefore a&#xD;
      relatively small amount of current to detect. A positive test for noninferiority will be&#xD;
      accompanied by the 95% confidence interval (0.025 in the hypothesized direction) for the&#xD;
      difference in means not including the noninferiority delta.&#xD;
&#xD;
      Secondary analysis will assess noninferiority of the bolus to the basal infusion method on&#xD;
      mean tolerance to cutaneous current across all time points measured, using a noninferiority&#xD;
      delta of 10 mA as above. In this repeated measures setting, noninferiority will be assessed&#xD;
      in the context of a linear mixed model adjusting for the within-subject correlation (using an&#xD;
      auto-regressive correlation structure). If the time-by-group interaction is non-significant&#xD;
      (P&gt;0.20) we will assess noninferiority collapsing over time and constructing a 1-tailed&#xD;
      t-test (using noninferiority delta of 10 mA) based on the model-based treatment effect for&#xD;
      bolus versus basal infusion. In presence of a group-time interaction noninferiority will be&#xD;
      assessed separately at each time point and a Holm-Bonferroni correction made for multiple&#xD;
      comparisons to maintain the hypothesis-wise type I error at 0.025.&#xD;
&#xD;
      We will also assess noninferiority of bolus to basal infusion on the secondary endpoint of&#xD;
      quadriceps femoris MVIC (22 hours total) using a mixed effects model as described above.&#xD;
&#xD;
      The rejection region for a noninferiority test includes superiority, by definition (i.e.,&#xD;
      &quot;not worse&quot; implies either equivalent or better). Therefore, if bolus is found to not only be&#xD;
      noninferior, but also superior, we will be able to claim superiority. This will be evidenced&#xD;
      by the 95% CI for the difference between means falling above zero.&#xD;
&#xD;
      Although we hypothesize that the bolus method will be noninferior to basal infusion, it is&#xD;
      possible that basal infusion would be noninferior to bolus. Therefore, we will also conduct&#xD;
      the above tests assessing noninferiority of basal infusion to bolus. If noninferiority is&#xD;
      found in both directions, we will claim equivalence at ±10mA. SAS software 9.3 (SAS&#xD;
      Institute, Cary, NC, USA) and R software versions 2.15.3 (The R Foundation for Statistical&#xD;
      Computing, Vienna, Austria) will be used for all analyses.&#xD;
&#xD;
      Sample Size Estimation. Sample size calculations are based on the primary aim of determining&#xD;
      the relationship between perineural ropivacaine delivery technique (basal vs. bolus) and&#xD;
      continuous adductor canal nerve block effects. To this end, we will perform a noninferiority&#xD;
      trial with the primary endpoint designated as the maximum tolerance to transcutaneous&#xD;
      electrical stimulation at Hour 8. With 24 subjects we will have approximately 90% power (88%)&#xD;
      at the 0.025 significance level to detect noninferiority of bolus ropivacaine to basal&#xD;
      infusion ropivacaine on mean tolerance to transcutaneous electrical stimulation at Hour 8&#xD;
      using an a priori noninferiority delta of 10 mA. Based on previously-published data, this&#xD;
      conservatively assumes a standard deviation of tolerance difference between legs of 15 mA.&#xD;
&#xD;
      We will apply the same analysis of percent change from baseline at Hour 0 to the secondary&#xD;
      outcome measures. We will also examine the time profiles of the responses over time with&#xD;
      spaghetti and mean plots. Further secondary analyses will include mixed-effects modeling of&#xD;
      the repeated hourly measures to confirm the analysis of percent change at 8 hours. These&#xD;
      models will account for the hierarchical correlation of paired measures from each subject&#xD;
      over time. We will use these models to test the effects of subject characteristics, including&#xD;
      handedness, sex, height, weight, body mass index, and age.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">August 2014</start_date>
  <completion_date type="Actual">December 2014</completion_date>
  <primary_completion_date type="Actual">December 2014</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>This is a split-body study in which each study subject receives both treatments: one on each side of the body. Which treatment is applied to which side of the body is randomized (and masked).</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
    <masking_description>The only individual aware of the treatment group assignments is the investigational pharmacist who has no interaction with the study subjects. Treatment group assignments were released by the investigational pharmacy only after completion of data collection.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Tolerance to Cutaneous Electrical Current</measure>
    <time_frame>After 8 h of infusion</time_frame>
    <description>Evaluated in the seated position using transcutaneous electrical stimulation (TES) in the same manner as described throughout the anesthesia literature (this is a &quot;gold standard&quot; 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.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Tolerance to Transcutaneous Electrical Current</measure>
    <time_frame>baseline through Hour 14 (except Hour 8 which is the primary outcome) and then again at Hour 22</time_frame>
    <description>Evaluated in the seated position using transcutaneous electrical stimulation (TES) in the same manner as described throughout the anesthesia literature (this is a &quot;gold standard&quot; 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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Maximum Voluntary Isometric Contraction of the Quadriceps</measure>
    <time_frame>Baseline and then every hour through Hour 14, as well as Hour 22</time_frame>
    <description>Strength of the quadriceps muscle was assessed by measurement of maximum voluntary isometric contraction. In the sitting position, without using accessory muscle groups, subjects performed maximum forceful knee extension against an electromechanical dynamometer (MicroFET2, Lafayette Instrument Company, Lafeyette, IN). The subject sat at the side of the bed with their legs dangling. The device was placed against the anterior tibia just above the malleoli between the subject and a nonelastic 5 cm-wide fabric band that was affixed to the gurney to stabilize the dynamometer during flexing of the quadriceps femoris muscle. Subjects were instructed to come to maximum force of knee extension over 2 seconds, hold this force for 5 seconds, and then relax. The maximum force was recorded, and results are reported relative to the pre-infusion baseline measurement (i.e., percent of baseline).</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">24</enrollment>
  <condition>Healthy Human Volunteers</condition>
  <arm_group>
    <arm_group_label>RIGHT side BOLUS and left side basal</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Bilateral adductor canal catheters were inserted and ropivacaine 0.2% administered concurrently. For the right catheter, the ropivacaine was administered as hourly bolus doses of 8 mL each a total of 8 times: one at time point zero and 1 on the hour for the following 7 hours. For the left catheter, the ropivacaine was administered as a continuous basal infusion (8 mL/h) from time point zero for the following 8 hours</description>
  </arm_group>
  <arm_group>
    <arm_group_label>RIGHT side BASAL and left side bolus</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Bilateral adductor canal catheters were inserted and ropivacaine 0.2% administered concurrently. For the right catheter, the ropivacaine was administered as a continuous basal infusion (8 mL/h) from time point zero for the following 8 hours. For the left catheter, the ropivacaine was administered as hourly bolus doses of 8 mL each a total of 8 times: one at time point zero and 1 on the hour for the following 7 hours.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Bolus</intervention_name>
    <description>An adductor canal catheter was inserted and ropivacaine 0.2% administered as hourly bolus doses of 8 mL each: one at time point zero and then on the hour for 7 additional doses.</description>
    <arm_group_label>RIGHT side BASAL and left side bolus</arm_group_label>
    <arm_group_label>RIGHT side BOLUS and left side basal</arm_group_label>
    <other_name>hourly bolus doses</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Basal</intervention_name>
    <description>An adductor canal catheter was inserted and ropivacaine 0.2% administered as a continuous basal infusion (8 mL/h) from time point zero for a total of 8 hours.</description>
    <arm_group_label>RIGHT side BASAL and left side bolus</arm_group_label>
    <arm_group_label>RIGHT side BOLUS and left side basal</arm_group_label>
    <other_name>continuous basal infusion</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  (1) age ≥ 18 years; and (2) willing to have bilateral adductor canal perineural&#xD;
             catheters placed with subsequent ropivacaine administration and motor/sensory testing&#xD;
             for 14 hours, requiring an overnight stay in the UCSD CTRI-CCR to allow dissipation of&#xD;
             local anesthetic infusion effects by the following morning.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  (1) current daily analgesic use; (2) opioid use within the previous 4 weeks; (3) any&#xD;
             neuro-muscular deficit of either femoral nerves and/or quadriceps muscles; (4) morbid&#xD;
             obesity [weight &gt; 35 kg/m2]; (5) pregnancy (as determined by a urine pregnancy test&#xD;
             prior to any study interventions); and (6) incarceration. We expect to recruit a&#xD;
             maximum of 30 healthy volunteers; with a target goal of 24 for the analysis. Selection&#xD;
             for inclusion will not be based on gender, race, or socioeconomic status. The study&#xD;
             population of interest includes men and women of all races and socioeconomic status.&#xD;
             There will be no participants from vulnerable populations, such as pregnant women,&#xD;
             children, or prisoners.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Brian M Ilfeld, MD, MS</last_name>
    <role>Principal Investigator</role>
    <affiliation>University California San Diego</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University California San Diego</name>
      <address>
        <city>San Diego</city>
        <state>California</state>
        <zip>92103</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <results_reference>
    <citation>Monahan AM, Sztain JF, Khatibi B, Furnish TJ, Jaeger P, Sessler DI, Mascha EJ, You J, Wen CH, Nakanote KA, Ilfeld BM. Continuous Adductor Canal Blocks: Does Varying Local Anesthetic Delivery Method (Automatic Repeated Bolus Doses Versus Continuous Basal Infusion) Influence Cutaneous Analgesia and Quadriceps Femoris Strength? A Randomized, Double-Masked, Controlled, Split-Body Volunteer Study. Anesth Analg. 2016 May;122(5):1681-8. doi: 10.1213/ANE.0000000000001182.</citation>
    <PMID>26863502</PMID>
  </results_reference>
  <verification_date>March 2021</verification_date>
  <study_first_submitted>August 14, 2014</study_first_submitted>
  <study_first_submitted_qc>August 15, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 18, 2014</study_first_posted>
  <results_first_submitted>July 17, 2019</results_first_submitted>
  <results_first_submitted_qc>March 18, 2021</results_first_submitted_qc>
  <results_first_posted type="Actual">March 19, 2021</results_first_posted>
  <last_update_submitted>March 18, 2021</last_update_submitted>
  <last_update_submitted_qc>March 18, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">March 19, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of California, San Diego</investigator_affiliation>
    <investigator_full_name>Brian M. Ilfeld, MD, MS</investigator_full_name>
    <investigator_title>Professor of Anesthesiology, In Residence</investigator_title>
  </responsible_party>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>

  <clinical_results>

    <participant_flow>
      <recruitment_details>This was a split-body study design, so while there were 24 human subjects involved; each had two treatments: one bolus and one basal. Therefore there were 24 sides receiving the &quot;bolus&quot; treatment and 24 sides receiving the &quot;basal&quot; treatment</recruitment_details>
      <group_list>
        <group group_id="P1">
          <title>Right Side Bolus, Left Side Basal</title>
          <description>The right side received ropivacaine 0.2% administration as repeated 8 mL bolus doses starting at time point 0 and given hourly for 7 additional doses. Since it is a split body study, the left side of the body of these participants received ropivacaine 0.2% perineural administration as a continuous basal infusion (8 mL/h) for 8 hours total.</description>
        </group>
        <group group_id="P2">
          <title>Right Side Basal, Left Side Bolus</title>
          <description>The right side received ropivacaine 0.2% administration as a continuous basal infusion (8 mL/h) for 8 hours total. Since it was a split body study, the left side of the body of these participants received ropivacaine 0.2% perineural administration as repeated 8 mL bolus doses starting at time point 0 and given hourly for 7 additional doses.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="13"/>
                <participants group_id="P2" count="11"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="13"/>
                <participants group_id="P2" count="11"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Right Side BOLUS and Left Side BASAL</title>
          <description>The right side received ropivacaine 0.2% administration as repeated 8 mL bolus doses starting at time point 0 and given hourly for 7 additional doses. Since it is a split body study, the left side of the body of these participants received ropivacaine 0.2% perineural administration as a continuous basal infusion (8 mL/h) for 8 hours total.</description>
        </group>
        <group group_id="B2">
          <title>Right Side BASAL and Left Side BOLUS</title>
          <description>The right side received ropivacaine 0.2% administration as a continuous basal infusion (8 mL/h) for 8 hours total. Since it was a split body study, the left side of the body of these participants received ropivacaine 0.2% perineural administration as repeated 8 mL bolus doses starting at time point 0 and given hourly for 7 additional doses.</description>
        </group>
        <group group_id="B3">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="13"/>
            <count group_id="B2" value="11"/>
            <count group_id="B3" value="24"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="13"/>
                    <count group_id="B2" value="11"/>
                    <count group_id="B3" value="24"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="13"/>
                    <measurement group_id="B2" value="11"/>
                    <measurement group_id="B3" value="24"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="13"/>
                    <count group_id="B2" value="11"/>
                    <count group_id="B3" value="24"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="10"/>
                    <measurement group_id="B2" value="7"/>
                    <measurement group_id="B3" value="17"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="4"/>
                    <measurement group_id="B3" value="7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race and Ethnicity Not Collected</title>
          <population>Race and Ethnicity were not collected from any participant.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="0"/>
                    <count group_id="B2" value="0"/>
                    <count group_id="B3" value="0"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>United States</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="13"/>
                    <count group_id="B2" value="11"/>
                    <count group_id="B3" value="24"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="13"/>
                    <measurement group_id="B2" value="11"/>
                    <measurement group_id="B3" value="24"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Height</title>
          <units>cm</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="13"/>
                    <count group_id="B2" value="11"/>
                    <count group_id="B3" value="24"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="173" spread="8"/>
                    <measurement group_id="B2" value="175" spread="10"/>
                    <measurement group_id="B3" value="174" spread="9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Weight</title>
          <units>kg</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="13"/>
                    <count group_id="B2" value="11"/>
                    <count group_id="B3" value="24"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="74" spread="12"/>
                    <measurement group_id="B2" value="79" spread="14"/>
                    <measurement group_id="B3" value="76" spread="13"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Dominant Leg was the RIGHT leg</title>
          <description>Just as with &quot;handedness&quot;, people have a dominant lower extremity, or leg--it is usually the leg that people use to kick a ball.</description>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="13"/>
                    <count group_id="B2" value="11"/>
                    <count group_id="B3" value="24"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="13"/>
                    <measurement group_id="B2" value="11"/>
                    <measurement group_id="B3" value="24"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Tolerance to Cutaneous Electrical Current</title>
        <description>Evaluated in the seated position using transcutaneous electrical stimulation (TES) in the same manner as described throughout the anesthesia literature (this is a &quot;gold standard&quot; 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.</description>
        <time_frame>After 8 h of infusion</time_frame>
        <group_list>
          <group group_id="O1">
            <title>BOLUS</title>
            <description>The right side received ropivacaine 0.2% administration as repeated 8 mL bolus doses starting at time point 0 and given hourly for 7 additional doses. Since it is a split body study, the left side of the body of these participants received ropivacaine 0.2% perineural administration as a continuous basal infusion (8 mL/h) for 8 hours total.</description>
          </group>
          <group group_id="O2">
            <title>BASAL</title>
            <description>The right side received ropivacaine 0.2% administration as a continuous basal infusion (8 mL/h) for 8 hours total. Since it was a split body study, the left side of the body of these participants received ropivacaine 0.2% perineural administration as repeated 8 mL bolus doses starting at time point 0 and given hourly for 7 additional doses.</description>
          </group>
        </group_list>
        <measure>
          <title>Tolerance to Cutaneous Electrical Current</title>
          <description>Evaluated in the seated position using transcutaneous electrical stimulation (TES) in the same manner as described throughout the anesthesia literature (this is a &quot;gold standard&quot; 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.</description>
          <units>mA</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="24"/>
                <count group_id="O2" value="24"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="26.6" spread="12.1"/>
                    <measurement group_id="O2" value="27.1" spread="14.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Tolerance to Transcutaneous Electrical Current</title>
        <description>Evaluated in the seated position using transcutaneous electrical stimulation (TES) in the same manner as described throughout the anesthesia literature (this is a &quot;gold standard&quot; 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.</description>
        <time_frame>baseline through Hour 14 (except Hour 8 which is the primary outcome) and then again at Hour 22</time_frame>
        <group_list>
          <group group_id="O1">
            <title>BOLUS</title>
            <description>Bilateral adductor canal catheters were inserted and ropivacaine 0.2% administered concurrently. For the right catheter, the ropivacaine was administered as hourly bolus doses of 8 mL each a total of 8 times: one at time point zero and 1 on the hour for the following 7 hours. For the left catheter, the ropivacaine was administered as a continuous basal infusion (8 mL/h) from time point zero for the following 8 hours&#xD;
Bolus: An adductor canal catheter was inserted and ropivacaine 0.2% administered as hourly bolus doses of 8 mL each: one at time point zero and then on the hour for 7 additional doses.&#xD;
Basal: An adductor canal catheter was inserted and ropivacaine 0.2% administered as a continuous basal infusion (8 mL/h) from time point zero for a total of 8 hours.</description>
          </group>
          <group group_id="O2">
            <title>BASAL</title>
            <description>Bilateral adductor canal catheters were inserted and ropivacaine 0.2% administered concurrently. For the right catheter, the ropivacaine was administered as a continuous basal infusion (8 mL/h) from time point zero for the following 8 hours. For the left catheter, the ropivacaine was administered as hourly bolus doses of 8 mL each a total of 8 times: one at time point zero and 1 on the hour for the following 7 hours.&#xD;
Bolus: An adductor canal catheter was inserted and ropivacaine 0.2% administered as hourly bolus doses of 8 mL each: one at time point zero and then on the hour for 7 additional doses.&#xD;
Basal: An adductor canal catheter was inserted and ropivacaine 0.2% administered as a continuous basal infusion (8 mL/h) from time point zero for a total of 8 hours.</description>
          </group>
        </group_list>
        <measure>
          <title>Tolerance to Transcutaneous Electrical Current</title>
          <description>Evaluated in the seated position using transcutaneous electrical stimulation (TES) in the same manner as described throughout the anesthesia literature (this is a &quot;gold standard&quot; 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.</description>
          <units>mA (milliamperes)</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="24"/>
                <count group_id="O2" value="24"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="26.7" spread="7.6"/>
                    <measurement group_id="O2" value="26.6" spread="7.2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Hour 1</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="26.8" spread="8.8"/>
                    <measurement group_id="O2" value="24.7" spread="7.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Hour 2</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="27.9" spread="9.0"/>
                    <measurement group_id="O2" value="27.4" spread="8.2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Hour 3</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="27.8" spread="9.6"/>
                    <measurement group_id="O2" value="29.7" spread="13.3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Hour 4</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="30.0" spread="14.0"/>
                    <measurement group_id="O2" value="29.7" spread="14.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Hour 5</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="29.5" spread="13.7"/>
                    <measurement group_id="O2" value="30.1" spread="14.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Hour 6</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="29.0" spread="14.0"/>
                    <measurement group_id="O2" value="29.0" spread="14.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Hour 7</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="26.8" spread="12.1"/>
                    <measurement group_id="O2" value="25.9" spread="11.3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Hour 9</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="22.7" spread="8.8"/>
                    <measurement group_id="O2" value="24.3" spread="10.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Hour 10</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="22.6" spread="8.6"/>
                    <measurement group_id="O2" value="24.9" spread="10.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Hour 11</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="21.1" spread="8.4"/>
                    <measurement group_id="O2" value="25.0" spread="12.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Hour 12</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="21.3" spread="7.8"/>
                    <measurement group_id="O2" value="24.6" spread="12.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Hour 13</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="21.2" spread="7.4"/>
                    <measurement group_id="O2" value="23.2" spread="9.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Hour 14</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="21.1" spread="7.9"/>
                    <measurement group_id="O2" value="22.3" spread="8.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Hour 22</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="24.1" spread="8.8"/>
                    <measurement group_id="O2" value="24.5" spread="9.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Maximum Voluntary Isometric Contraction of the Quadriceps</title>
        <description>Strength of the quadriceps muscle was assessed by measurement of maximum voluntary isometric contraction. In the sitting position, without using accessory muscle groups, subjects performed maximum forceful knee extension against an electromechanical dynamometer (MicroFET2, Lafayette Instrument Company, Lafeyette, IN). The subject sat at the side of the bed with their legs dangling. The device was placed against the anterior tibia just above the malleoli between the subject and a nonelastic 5 cm-wide fabric band that was affixed to the gurney to stabilize the dynamometer during flexing of the quadriceps femoris muscle. Subjects were instructed to come to maximum force of knee extension over 2 seconds, hold this force for 5 seconds, and then relax. The maximum force was recorded, and results are reported relative to the pre-infusion baseline measurement (i.e., percent of baseline).</description>
        <time_frame>Baseline and then every hour through Hour 14, as well as Hour 22</time_frame>
        <group_list>
          <group group_id="O1">
            <title>BOLUS</title>
            <description>The right side received ropivacaine 0.2% administration as repeated 8 mL bolus doses starting at time point 0 and given hourly for 7 additional doses. Since it is a split body study, the left side of the body of these participants received ropivacaine 0.2% perineural administration as a continuous basal infusion (8 mL/h) for 8 hours total.</description>
          </group>
          <group group_id="O2">
            <title>BASAL</title>
            <description>The right side received ropivacaine 0.2% administration as a continuous basal infusion (8 mL/h) for 8 hours total. Since it was a split body study, the left side of the body of these participants received ropivacaine 0.2% perineural administration as repeated 8 mL bolus doses starting at time point 0 and given hourly for 7 additional doses.</description>
          </group>
        </group_list>
        <measure>
          <title>Maximum Voluntary Isometric Contraction of the Quadriceps</title>
          <description>Strength of the quadriceps muscle was assessed by measurement of maximum voluntary isometric contraction. In the sitting position, without using accessory muscle groups, subjects performed maximum forceful knee extension against an electromechanical dynamometer (MicroFET2, Lafayette Instrument Company, Lafeyette, IN). The subject sat at the side of the bed with their legs dangling. The device was placed against the anterior tibia just above the malleoli between the subject and a nonelastic 5 cm-wide fabric band that was affixed to the gurney to stabilize the dynamometer during flexing of the quadriceps femoris muscle. Subjects were instructed to come to maximum force of knee extension over 2 seconds, hold this force for 5 seconds, and then relax. The maximum force was recorded, and results are reported relative to the pre-infusion baseline measurement (i.e., percent of baseline).</description>
          <units>percentage of baseline MVIC</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="24"/>
                <count group_id="O2" value="24"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="188" spread="65"/>
                    <measurement group_id="O2" value="188" spread="78"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Hour 1</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="84" spread="27"/>
                    <measurement group_id="O2" value="88" spread="36"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Hour 2</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="89" spread="21"/>
                    <measurement group_id="O2" value="87" spread="30"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Hour 3</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="95" spread="25"/>
                    <measurement group_id="O2" value="93" spread="32"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Hour 4</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="92" spread="34"/>
                    <measurement group_id="O2" value="87" spread="31"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Hour 5</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="95" spread="38"/>
                    <measurement group_id="O2" value="90" spread="29"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Hour 6</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="88" spread="34"/>
                    <measurement group_id="O2" value="93" spread="91"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Hour 7</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="85" spread="35"/>
                    <measurement group_id="O2" value="92" spread="29"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Hour 8</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="88" spread="31"/>
                    <measurement group_id="O2" value="94" spread="32"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Hour 9</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="86" spread="30"/>
                    <measurement group_id="O2" value="87" spread="30"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Hour 10</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="89" spread="36"/>
                    <measurement group_id="O2" value="90" spread="32"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Hour 11</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="89" spread="36"/>
                    <measurement group_id="O2" value="87" spread="30"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Hour 12</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="87" spread="35"/>
                    <measurement group_id="O2" value="84" spread="29"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Hour 13</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="84" spread="32"/>
                    <measurement group_id="O2" value="89" spread="31"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Hour 14</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="85" spread="30"/>
                    <measurement group_id="O2" value="88" spread="29"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Hour 22</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="114" spread="35"/>
                    <measurement group_id="O2" value="119" spread="39"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>22 hours after intervention</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Bolus</title>
          <description>ropivacaine 0.2% administration as repeated, scheduled (one/h) bolus doses (8 mL) x8 h&#xD;
ropivacaine</description>
        </group>
        <group group_id="E2">
          <title>Basal</title>
          <description>ropivacaine 0.2% administration as a continuous basal infusion (8 mL/h) x8 h&#xD;
ropivacaine</description>
        </group>
      </group_list>
      <serious_events>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="24"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Dr Brian Ilfeld</name_or_title>
      <organization>UCSD</organization>
      <phone>(619) 543-5560</phone>
      <email>bilfeld@ucsd.edu</email>
    </point_of_contact>
  </clinical_results>
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02219438
org study id: Adductor Canal Basal vs Bolus
nct id: NCT02219438
lead sponsor: 
has dmc: No
Patients usually experience moderate-to-severe pain following the knee replacement that is
      often treated with a femoral nerve block (injection of numbing medicine placed around the
      main nerve of the knee joint). To make the nerve block last longer, a tiny tube is often
      placed next to the nerve and numbing medicine is infused for multiple days. However, while
      the numbing medicine takes away pain, it also decreases sensations, muscle strength, and
      proprioception (knowing where the leg is in space without looking at it) which greatly
      increases the risk of falling. Since falling can be catastrophic following major surgery, a
      femoral nerve blocks are being phased out by surgeons and anesthesiologists. The
      most-promising replacement is called an adductor canal nerve block. For this new type of
      block, a perineural catheter is inserted into a small canal in the middle of the upper leg.
      This canal contains the sensory nerve fibers leading to the knee, and only a single nerve
      that serves a relatively small muscle. Multiple studies have demonstrated a dramatic increase
      in muscle strength using the new adductor canal block compared with the traditional femoral
      block. However, practitioners perceptions of the new block is that it provides insufficient
      pain control following knee arthroplasty, even though all of the sensory nerves affected with
      the femoral block are also-theoretically-affected with the adductor canal block. One reason
      for this difference may be the small canal of the latter which is a relatively tight area in
      which the numbing medicine might not spread particularly well (due to pressure from
      surrounding tissues). One way to possibly counter this issue is by providing repeated boluses
      of the numbing medicine that will improve the medicine's spread relative to a
      more-traditional slow, continuous ("basal") infusion. This study seeks to compare these two
      techniques of medication administration through perineural adductor canal catheters:

      Our primary aim is to test the hypothesis that, for continuous adductor canal blocks,
      providing local anesthetic as repeated, hourly bolus doses results in an increased sensory
      block compared with providing local anesthetic as a continuous basal infusion at an
      equivalent hourly dose.

      As a secondary aim, we hypothesize that, for continuous adductor canal blocks, providing
      local anesthetic as repeated, hourly bolus doses results in either equivalent or less motor
      block compared with providing local anesthetic as a continuous basal infusion at an
      equivalent hourly dose.
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.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: This is a split-body study in which each study subject receives both treatments: one on each side of the body. Which treatment is applied to which side of the body is randomized (and masked).
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
masking description: The only individual aware of the treatment group assignments is the investigational pharmacist who has no interaction with the study subjects. Treatment group assignments were released by the investigational pharmacy only after completion of data collection.
measure: Tolerance to Cutaneous Electrical Current
time frame: After 8 h of infusion
description: 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.
measure: Tolerance to Transcutaneous Electrical Current
time frame: baseline through Hour 14 (except Hour 8 which is the primary outcome) and then again at Hour 22
description: 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.
measure: Maximum Voluntary Isometric Contraction of the Quadriceps
time frame: Baseline and then every hour through Hour 14, as well as Hour 22
description: Strength of the quadriceps muscle was assessed by measurement of maximum voluntary isometric contraction. In the sitting position, without using accessory muscle groups, subjects performed maximum forceful knee extension against an electromechanical dynamometer (MicroFET2, Lafayette Instrument Company, Lafeyette, IN). The subject sat at the side of the bed with their legs dangling. The device was placed against the anterior tibia just above the malleoli between the subject and a nonelastic 5 cm-wide fabric band that was affixed to the gurney to stabilize the dynamometer during flexing of the quadriceps femoris muscle. Subjects were instructed to come to maximum force of knee extension over 2 seconds, hold this force for 5 seconds, and then relax. The maximum force was recorded, and results are reported relative to the pre-infusion baseline measurement (i.e., percent of baseline).
arm group label: RIGHT side BOLUS and left side basal
arm group type: Experimental
description: Bilateral adductor canal catheters were inserted and ropivacaine 0.2% administered concurrently. For the right catheter, the ropivacaine was administered as hourly bolus doses of 8 mL each a total of 8 times: one at time point zero and 1 on the hour for the following 7 hours. For the left catheter, the ropivacaine was administered as a continuous basal infusion (8 mL/h) from time point zero for the following 8 hours
arm group label: RIGHT side BASAL and left side bolus
arm group type: Active Comparator
description: Bilateral adductor canal catheters were inserted and ropivacaine 0.2% administered concurrently. For the right catheter, the ropivacaine was administered as a continuous basal infusion (8 mL/h) from time point zero for the following 8 hours. For the left catheter, the ropivacaine was administered as hourly bolus doses of 8 mL each a total of 8 times: one at time point zero and 1 on the hour for the following 7 hours.
intervention type: Drug
intervention name: Bolus
description: An adductor canal catheter was inserted and ropivacaine 0.2% administered as hourly bolus doses of 8 mL each: one at time point zero and then on the hour for 7 additional doses.
arm group label: RIGHT side BASAL and left side bolus
arm group label: RIGHT side BOLUS and left side basal
other name: hourly bolus doses
intervention type: Drug
intervention name: Basal
description: An adductor canal catheter was inserted and ropivacaine 0.2% administered as a continuous basal infusion (8 mL/h) from time point zero for a total of 8 hours.
arm group label: RIGHT side BASAL and left side bolus
arm group label: RIGHT side BOLUS and left side basal
other name: continuous basal infusion
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: Accepts Healthy Volunteers
last name: Brian M Ilfeld, MD, MS
role: Principal Investigator
affiliation: University California San Diego
facility: 
country: United States
citation: Monahan AM, Sztain JF, Khatibi B, Furnish TJ, Jaeger P, Sessler DI, Mascha EJ, You J, Wen CH, Nakanote KA, Ilfeld BM. Continuous Adductor Canal Blocks: Does Varying Local Anesthetic Delivery Method (Automatic Repeated Bolus Doses Versus Continuous Basal Infusion) Influence Cutaneous Analgesia and Quadriceps Femoris Strength? A Randomized, Double-Masked, Controlled, Split-Body Volunteer Study. Anesth Analg. 2016 May;122(5):1681-8. doi: 10.1213/ANE.0000000000001182.
PMID: 26863502
responsible party type: Principal Investigator
investigator affiliation: University of California, San Diego
investigator full name: Brian M. Ilfeld, MD, MS
investigator title: Professor of Anesthesiology, In Residence
sharing ipd: No
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 