Clinical trial NCT02662023
Conditions: Postoperative Pain
Keywords: Healthy Human Volunteers
Sponsor: University of California, San Diego
Start date: 2016-02-01; Completion date: 2016-06-01
Enrollment: 24 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Single-injection transversus abdominis plane (TAP) blocks have been used to treat postoperative pain, and are become very popular within the United States because of their high analgesic potency and relative ease of placement. Unfortunately, the longest local anesthetic available lasts only 8-12 hours. Continuous TAP blocks-also termed "perineural infusion"-involve bathing the multiple nerves of the abdominal wall in local anesthetic using a percutaneously-inserted perineural catheter inserted just anterior (ventral) and cephalad to the anterior superior iliac spine. For most catheter locations, an infusion is preferred to a single-injection nerve block because the duration of analgesia may be extended to better match the duration of surgical pain. But, unlike brachial plexus, femoral, and sciatic nerve perineural infusion, a continuous basal infusion of local anesthetic does not provide adequate analgesia for TAP catheters. This may be due to the fact that the TAP is a relatively tight space, so it might require a bolus of fluid to adequately spread the perineural local anesthetic to the multiple required nerves (as evidence of this, single-injection TAP blocks are very effective, although with a limited duration). The result is that while single-injection TAP blocks are widely used, TAP catheters have not been adopted. This scenario leaves surgical pain untreated following the resolution of the single-injection TAP block. The recent development of an infusion pump that can automatically deliver repeated bolus doses may allow the spread of local anesthetic to the multiple sensory nerves necessary to provide adequate analgesia, with a duration that better matches postoperative requirements. The investigators therefore propose a randomized, double-masked, controlled trial to determine if delivering local anesthetic as a repeated bolus dose results in improved local anesthetic spread/effects compared with a continuous basal infusion for TAP catheters.

Detailed description:
This investigation will be a randomized, observer-masked, controlled, split-body, human-subjects clinical trial. Of note, the investigators 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.

Volunteers will be solicited using the CTRI Research Match and an existing database of volunteers (IRB approved). If a volunteer meets inclusion/exclusion criteria (see Eligibility Criteria) and desires study participation, written, informed consent will be obtained using a UCSD IRB-approved/stamped ICF. 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.

Perineural catheter insertion: Following written, informed consent, subjects will be admitted to the UCSD CTRI Center for Clinical Research Services (CCR) 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). Bilateral TAP perineural catheters (FlexBlock, Teleflex Medical, Reading, PA, USA) will be inserted using ultrasound guidance using a technique previously described. To check the perineural catheter placement accuracy, 5 mL of normal saline will be administered via the catheters under ultrasound guidance with the definition of a successful catheter insertion an increase in fluid volume within the TAP (the plane between the transversus abdominis muscle and internal oblique muscle). Inaccurately inserted catheters will be replaced.

Treatment Group Assignment: Subjects will act as their own controls: the right side will be randomized to one of two treatment groups: ropivacaine 0.2% administration as either a basal infusion (8 mL/h) or bolus doses (24 mL administered every 3 hours). The left side will receive the other possible treatment. Randomization will be based on computer-generated codes. Randomization will be in blocks of four. An infusion pump with study infusate will be attached to each of the perineural catheters and initiated at Hour 0. Which side of the participant's body will receive the basal rate and which side will receive bolus volume will depend upon the treatment group assignment but the total dose of local anesthetic is the same for each side.

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 24 mL bolus dose every 3 hours beginning at Hour 0. Perineural catheters will be removed after 6 hours (a total of 2 bolus doses).

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 catheter withdrawal.

Outcome measurements: At all time points, the right side will be measured first, followed by the left side (subjects in the supine position).

Measurements will be performed at baseline (prior to local anesthetic administration), after 6 hours of administration, and at each hour in between for a total of 7 time points:

* Hour 0 (baseline) just prior to local anesthetic administration
* Hours 1 and 2
* Hour 3, just prior to the scheduled bolus dose at Hour 3
* Hours 4 and 5
* Hour 6

The sensory deficit will be measured using two methods:

* von Frey filaments (mechanical detection threshold)
* Cold roller (cold deficit)

The sensory deficit will be measured along two separate anatomical lines at each time point:

* The mid-axillary "vertical" line (measuring cephalad-caudad effects)
* A transverse "horizontal" line passing through the anterior superior iliac spine (measuring anterior-posterior effects)

Statistical analysis: The investigators' calculations are focused on the primary hypothesis that when using transversus abdominis plane (TAP) block perineural catheters, providing local anesthetic in repeated bolus doses increases the cephalad-caudad local anesthetic effects compared with a basal-only infusion of the same volume and dose of local anesthetic. To measure cephalad-caudad local anesthetic effects, we will measure the cephalad-caudad sensory deficit to cold temperature in centimeters along the mid-axillary line. The primary end point will be this measurement after 6 hours of local anesthetic administration (6 hours of a continuous basal infusion or 2 bolus doses at 3-hour increments, the last being 3 hours prior to the measurement of the primary endpoint). Each subject will act as their own control with each side receiving a different treatment. Normality of distribution will be determined using the Shapiro-Wilk normality test (Prism 6, GraphPad, San Diego, California). For normally distributed data, comparisons for parametric and nonparametric data will be tested using the t-test or Mann-Whitney test and presented as mean (SD) or median \[interquartile\], respectively. Nominal data will be analyzed using the Pearson Chi square test. P\<0.05 will be considered significant.

Sample size estimation: With 21 evaluable subjects we will have 80% power at the 0.05 significance level to detect the superiority of the administration of local anesthetic as repeated bolus doses as compared with a continuous basal infusion at Hour 6 (primary outcome). Using an expected standard deviation of 7 cm for the primary endpoint, and given a 2-sided Type I error protection of 0.05 and power=0.80, approximately 21 subjects in each treatment arm will be required to detect a difference between treatment group means of 6 cm. Since this is a split-body study design and each subject will have one of each treatments on opposite sides of the body, 21 subjects total will produce 21 subjects in each treatment arm. The investigators chose 6 cm as a detectable treatment difference because a 3 cm distance is approximately equivalent to the width of one dermatome, and the vast majority of anesthesiologists would consider a 2-dermatome difference clinically significant. To allow for a larger-than-anticipated standard deviations, smaller-than-anticipated difference between treatment means, drop out subjects, or failed catheters, the investigators will enroll a total of 24 subjects.

Arms: arm 1: Bilateral transversus abdominis catheters were inserted and ropivacaine 0.2% administered concurrently. For the right catheter, the ropivacaine was administered as two separate bolus doses of 24 mL each: one at time point zero and one 3 hours later. For the left catheter, the ropivacaine was administered as a continuous basal infusion (8 mL/h) from time point zero for the following 6 hours arm 2: Bilateral transversus abdominis 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 6 hours. For the left catheter, the ropivacaine was administered as two separate bolus doses of 24 mL each: one at time point zero and one 3 hours later
Interventions: intervention 1: Bolus intervention 2: Basal
Intervention descriptions: intervention 1: A transversus abdominis catheter was inserted and ropivacaine 0.2% administered as two separate bolus doses of 24 mL each: one at time point zero and one 3 hours later. intervention 2: A transversus abdominis catheter was inserted and ropivacaine 0.2% administered as a continuous basal infusion (8 mL/h) from time point zero for the following 6 hours.

Protocol documents: