Continuous Peripheral Nerve Blocks: Is Local Anesthetic Dose the Only Factor, or Do Concentration and Volume Influence Infusion Effects as Well?

• ❖ Whether the main determinant of continuous peripheral nerve block effects is local anesthetic concentration and volume or simply total drug dose is unknown

• ❖ After hip arthroplasty, patients with continuous lumbar plexus nerve blocks required the same milligram per hour of ropivacaine in a dilute (0.1%) solution as in a concentrated one (0.4%) and had the same degree of motor block.

• ❖ Over these concentrations and conditions, lower ropivacaine concentration did not result in less motor block

CONTINUOUS peripheral nerve blockade involves the percutaneous insertion of a catheter directly adjacent to a peripheral nerve. The catheter is then infused with local anesthetic resulting in potent, site-specific analgesia (among other benefits) that lasts well beyond the normal duration of a single-injection nerve block.1,2However, one well-recognized side effect is muscular weakness,3particularly undesirable in the continuous psoas compartment and femoral nerve blocks that affect quadriceps femoris function required for ambulation. Considering that these perineural infusions are often provided for analgesia after hip2,4and knee1,5surgical procedures in elderly patients,6,7and in this patient population a fall may prove catastrophic, it is imperative that any risks be minimized.

Because quadriceps femoris weakness is associated with significant functional disability8and an increased risk of falls in elderly patients,9it is postulated that any nerve block-induced muscular weakness is best minimized during perineural local anesthetic infusion.10Many different local anesthetic concentration and basal-rate combinations have been proposed: for ropivacaine alone, concentrations have included 0.1%,110.15%,120.2%,130.25%,140.3%,15and 0.4%.16However, optimizing infusion characteristics is difficult, given that it is currently unknown whether the primary determinant of continuous peripheral nerve block effects is simply total drug dose (mass) or whether local anesthetic concentration or volume exert an additional influence.

We therefore tested the hypothesis that providing ropivacaine at different concentrations and rates (0.1% at 12 ml/h vs.  0.4% at 3 ml/h)—but at an equivalent total basal (12 mg/h) and patient-controlled bolus doses (4 mg)—produces comparable effects when used in continuous posterior lumbar plexus blocks after hip arthroplasty. The primary endpoint was the difference in maximum voluntary isometric contraction (MVIC) of the quadriceps the morning after surgery compared with the preoperative MVIC, expressed as a percentage of the preoperative MVIC. Secondary endpoints included hip adductor and hip flexor MVIC changes, sensory changes in the femoral nerve distribution, hip range-of-motion, ambulatory ability, pain scores, and ropivacaine consumption.

The local Institutional Review Board (University of California San Diego, San Diego, CA) approved all study procedures. The trial was prospectively registered at clinicaltrials. gov (NCT00912873). Patients offered enrollment included adults (≥18 yr) scheduled for primary, unilateral hip arthroplasty via  a 15–25-cm curvilinear lateral skin incision centered over the greater trochanter (either hip resurfacing or hip replacement via  the posterior approach with a posterior capsulotomy) who desired a continuous posterior lumbar plexus block for postoperative analgesia. Exclusion criteria included a history of opioid dependence or abuse, current chronic analgesic therapy (daily use > 20 mg oxycodone-equivalent opioid use within the 2 weeks before surgery and duration of use > 4 weeks), allergy to study medications, known hepatic or renal insufficiency/disease, peripheral neuropathy of the surgical extremity, body mass index > 40 kg/m², pregnancy, or incarceration.

All participants provided written, informed consent before any study procedures. Before surgery, subjects had baseline endpoints measured (endpoint details provided below) by a single physical therapist (L.K.M.). Subjects were then placed in the lateral decubitus position with the operative hip up. Intravenous fentanyl and midazolam were titrated for patient comfort. The area that would be subsequently covered by the catheter dressing and tape was prepared with chlorhexidine gluconate and isopropyl alcohol (ChloraPrep One-Step, Medi-Flex Hospital Products, Inc., Overland Park, KS) and then shaved with a surgical hair clipper, if necessary. After sterile preparation (additional ChloraPrep One-Step) and draping, a local anesthetic skin wheal was raised at the needle entry point similar to previously described landmarks.4With the bevel-directed caudad, a 102- or 152-mm, 18-gauge, insulated needle (Contiplex, B. Braun Medical, Inc., Bethlehem, PA) was inserted with the long axis perpendicular to the skin. This needle was connected to a nerve stimulator (Stimuplex-DIG, B. Braun Medical, Inc.) initially set at 1.2 mA, 0.1 ms, and 2 Hz. With gentle aspiration applied to aid in identification of a penetrated vessel, the needle was redirected, as needed, until quadriceps contractions and patellar motion were elicited with a stimulating current of 0.20–0.40 mA.

Subsequently, 15 ml of D⁵W was injected in divided doses. The standard multiorifice perineural catheter that came packaged with the needle was replaced with a similar catheter with only a single orifice at its tip (B. Braun Medical Inc.). The catheter was advanced 1 cm past the needle tip and the needle withdrawn over the catheter. If the catheter met resistance at the needle tip, the catheter tip was left at the needle tip location and the needle withdrawn over the catheter. In both cases, the catheter was inserted an additional 2 cm while holding the needle stationary once the needle tip had been withdrawn at least 3 cm from its original location. The injection port was attached to the catheter and the catheter secured with sterile liquid adhesive, an occlusive dressing, tape, and an anchoring device on the ipsilateral shoulder.17 

Fifteen milliliters of 2% mepivacaine with epinephrine (5 μg/ml) was slowly injected via  the catheter with gentle aspiration every 3 ml. Catheter placement was considered successful if, within 15 min, the patient experienced a decreased sensation to cold temperature over the ipsilateral distal thigh and weakness upon knee extension. Patients without a successful nerve block had their catheters replaced or were withdrawn from the study.

Remaining patients were randomized to one of the two treatment groups—ropivacaine 0.1 or 0.4%—in blocks of four, stratified by hip arthroplasty procedure (either total or resurfacing) using computer-generated tables available only to the Investigational Drug Service. The basal rate and patient-controlled bolus volume depended on the treatment group (table 1). Although the basal rate and bolus volume differed for each concentration, the total dose of local anesthetic was the same for all patients. A portable electronic infusion pump (Pain Pump 2 Blockaid, Stryker Instruments, Kalamazoo, MI) was filled with study infusate and programmed by investigational pharmacists and delivered to the operating room of each subject. Although patients were not specifically informed of their ropivacaine concentration, the infusion pumps that were accessible to subjects revealed enough information that subjects should not be considered masked to treatment group.

Patients were administered a standardized general anesthetic using inhaled sevoflurane, nitrous oxide, and oxygen during surgery. The ropivacaine infusion was initiated via  the perineural catheter before the end of surgery, with the exact time recorded for study purposes. Intravenous fentanyl (25 μg increments) was administered as needed during surgery; intravenous morphine sulfate was titrated to a respiratory rate of 12–14 just before emergence.

In addition to the ropivacaine perineural infusion initiated in the operating room and continued at least through postoperative day 2, all patients were provided oral acetaminophen (975 mg every 6 h), celecoxib (200 mg every 12 h), and sustained-release oxycodone (OxyContin, 10 mg every 12 h). For breakthrough pain, patients were instructed to depress the bolus button on their pump and wait 15 min for the effect. Rescue opioid and route of administration were titrated to pain severity using a numeric rating scale (NRS) of 0–10, with 0 equal to no pain and 10 being the worst imaginable pain; mild pain (NRS < 4): oral oxycodone 5 mg, moderate pain (NRS 4–7): oral oxycodone 10 mg, and severe pain (NRS > 7): intravenous morphine 2–4 mg.

Infusion pumps for subsequent days, prepared by the investigational drug service, were provided to replace the initial pumps on postoperative day 1 after the morning physical therapy session, and the precise time and pump information were recorded. These replacement infusion pumps contained the same infusate and programming as the initial pumps and were provided to ensure uninterrupted perineural infusion for at least the first 48 postoperative hours.

We selected measures that have established reliability and validity.9,18–22A single investigator (L.K.M.), masked to treatment group assignment, performed all physical therapy measures and assessments to avoid interrater discordance. Postoperative measurements were performed the day after surgery in both the morning and afternoon.

We evaluated muscle strength with an isometric force electromechanical dynamometer (MicroFET2, Lafayette Instrument Company, Lafayette, IN) to measure the force produced during an MVIC.20For quadriceps and hip adductor evaluation, subjects were placed in seated position and the knee flexed at 90°, whereas for hip flexor evaluation, subjects were placed in supine position. For quadriceps evaluation, the dynamometer was placed on the ipsilateral anterior tibia perpendicular to the tibial crest just proximal to the medial malleolus.19,20,23The primary endpoint was the difference in quadriceps MVIC the morning after surgery compared with the preoperative MVIC, expressed as a percentage of the preoperative MVIC: ([preoperative MVIC − postoperative MVIC]/preoperative MVIC) × 100.9This calculation allowed patients to act as their own controls.9For hip adductor evaluation, the femoral shaft was held at 30° off midline and the dynamometer placed over the medial femoral epicondyle (adductor tubercle). For hip flexor evaluation, the hip was held fully extended and the dynamometer placed over the quadriceps femoris tendon just proximal to the patella. For all measurements, subjects were asked to take 2 s to come to maximum effort by contracting the target muscle(s), maintain this effort for 5 s, and then relax.23 

We evaluated femoral nerve tolerance to transcutaneous electrical stimulation with the same quantitative procedure as the one described previously.18Electrocardiogram pads were placed over the proximal patella and quadriceps tendon and attached to a nerve stimulator (Model NS252; Fisher & Paykel, Auckland, New Zealand). The current was increased from 0 mA until subjects described mild discomfort at which time the current was recorded as the tolerated level and the nerve stimulator turned off.

We evaluated ambulatory ability using the 30-m walking test and 6-min walk test.21The 30-m walking test simply measures the amount of time it takes patients to ambulate 100 ft. After patients ambulated 100 ft, they were instructed to continue walking and the total distance covered in the first 6 min was recorded as the result of the 6-min walk test.21Patients were allowed to slow or stop and rest during the walk but were asked to resume walking as soon as they felt they were able to. The maximum ambulatory distance was also recorded.

We evaluated hip range-of-motion using standard goniometry for passive hip flexion with patients in the supine position before ambulation. A maximum of 90° was permitted to decrease the risk of femoral head dislocation.

We evaluated all pain measurements using the 0–10 NRS.22Pain scores were recorded immediately after physical therapy, every 4 h (except when patients were sleeping), and when patients requested analgesics.

Sample size calculations were centered around our primary hypothesis that differing the concentration (0.1 vs.  0.4%) while providing an equal total dose of ropivacaine through a psoas compartment catheter after hip arthroplasty has no impact on the percentage of quadriceps muscle strength retained the morning after surgery compared with preoperative strength (expressed as a percentage of the preoperative MVIC).9We considered a difference of 15% points to be clinically relevant because a 10% side-to-side strength difference is common, yet functionally unnoticeable in healthy individuals.24,25With an SD of each group of 17 (based on unpublished data, Brian Ilfeld, M.D., M.S., San Diego, California, March 2008) and assuming a two-sided type I error protection of 0.05 and a power of 0.80, approximately 21 patients in each group were required (StatMate 2.0; GraphPad Software, San Diego, CA). To allow for a larger SD than anticipated or potential drop-out, we randomized 25 subjects per group.

Because the aim of the study was to evaluate equivalency (because of a proposed hypothesis of no group effect), standard inferential statistics used to demonstrate statistically significant nonzero effects do not strictly apply. Instead, we used the method described by Armitage et al.  26for equivalency trials, whereby we conclude equivalence if the 95% confidence interval for the difference falls within a tolerated interval (R Software Environment for Statistical Computing, R Foundation for Statistical Computing, Vienna, Austria). We assessed the equivalency of the effect of differing concentrations (0.1 vs.  0.4%) of ropivacaine on the percentage drop in quadriceps muscle strength as measured by MVIC by a nonparametric 95% confidence interval.27,28If the confidence interval fell within −15 to 15% range, we concluded that the effect of the concentrations were equivalent. We also summarized and tested for differences in demographic and clinical variables between the two concentrations by Wilcoxon Mann–Whitney rank sum test (for continuous variables) and Fisher exact test (for categorical variables).

During a 12-month period beginning June 2008, 56 patients were enrolled in this study. Three subjects were withdrawn from the study before catheter insertion (exclusion criteria identified after enrollment but before randomization). Of the remaining 53 subjects, 50 had a psoas compartment perineural catheter successfully inserted per protocol (in three subjects, an evoked motor response could not be elicited at a current <0.5 mA as required by the study protocol). All 50 subjects exhibited a sensory and motor block within 15 min after being given a local anesthetic bolus via  the catheter. Subjects were randomized to one of the two treatment groups, and these two groups were similar in demographic, anthropometric, and surgical characteristics (table 2).

Quadriceps MVIC for patients receiving 0.1% ropivacaine (n = 26) declined by a mean (SE) of 64.1% (6.4) versus  68.0% (5.4) for patients receiving 0.4% ropivacaine (n = 24) between the preoperative period and the day after surgery (95% CI for the group difference: −8.0 to 14.4%; P = 0.70). Because the confidence interval falls within the prespecified −15 to 15% range, we found that the effect of the two concentrations on quadriceps MVIC was equivalent.

The 95% confidence intervals for the estimated group differences in quadriceps femoris (fig. 1), hip adductor (fig. 2), or hip flexor strength (fig. 3) or tolerance of transcutaneous electrical stimulation in the cutaneous distribution of the femoral nerve (fig. 4) all fell within prespecified tolerances and were therefore deemed equivalent. The amount of ropivacaine delivered was 13.0 (0.8) mg/h for patients receiving 0.1% ropivacaine compared with 13.2 (0.9) mg/h for patients receiving 0.4% ropivacaine (P = 0.83). Total intravenous morphine equivalents were 26 (3) and 26 (4) mg for patients receiving 0.1 and 0.4%, respectively (P = 0.35). There was no statistically significant difference between groups in any of the additional secondary endpoints (table 3). There were no patient falls in either treatment group, and no patient required a decrease in their basal infusion rate because of quadriceps weakness.

This investigation provides evidence that local anesthetic concentration and volume do not influence the effects of continuous posterior lumbar plexus nerve blocks. This finding suggests that local anesthetic dose (mass) is the primary determinant of perineural infusion effects. Three previous studies investigated this topic involving popliteal,29infraclavicular,30and interscalene31perineural infusion. However, those reports failed to provide a definitive answer because of two protocol limitations common to all three studies: (1) the primary endpoint—the incidence of an insensate extremity over a 24-h period—lacked objective measurement and had not been previously validated; (2) the number of patient-controlled bolus doses administered was unavailable; therefore, the total hourly local anesthetic dose could not be calculated. This study was specifically designed to correct these weaknesses: (1) the primary outcome variable—quadriceps femoris MVIC—is a validated, reproducible, objective endpoint9,19,20,23; (2) the total hourly local anesthetic consumption was available from the portable electronic infusion pumps.32There are additional dose-response studies involving continuous peripheral nerve blocks.13,33–37However, these studies varied either local anesthetic concentration or rate/volume while holding the other constant, resulting in differing drug doses.13,34–37When both variables were allowed to vary, an equal mass among groups was not required.33Our study is thus unique in that it varied both concentration and infusion rate in a static ratio so that the total dose from the basal infusion was comparable in each treatment group and corrected for previous weaknesses in similar studies. This allowed for the first valid examination of the relative importance of local anesthetic dose compared with concentration/volume during perineural infusion.

The relative importance of local anesthetic concentration/volume versus  dose has significant clinical consequence, given the wide range of local anesthetic concentrations the investigators have used for perineural infusion.11–13,15,16The issue has particular importance for lower extremity perineural infusions. Although inhibition of pain fibers is the primary goal for postoperative continuous peripheral nerve blocks, currently available local anesthetics approved for clinical use decrease other afferent (e.g. , nonpain-related sensory and proprioception) and efferent (e.g. , motor) nerve fibers as well,38resulting in undesirable side effects such as muscular weakness.3There is growing evidence that lower extremity continuous peripheral nerve blocks may increase the risk of patient falls,2,5,34,39,40although to what degree the perineural local anesthetic infusion was a contributing factor in these cases remains unknown because the studies were neither designed nor powered to detect such (presumably) rare complications. Nonetheless, patient falls during perineural infusion are now being highlighted in the surgical and anesthesiology literature.10,39 

Related to the issue of infusion-induced muscle weakness, in a previous study involving continuous femoral nerve blocks after knee arthroplasty, 43% of patients receiving 0.2% ropivacaine at 8 ml/h (vs.  12% of patients receiving perineural saline) required a decrease in their basal infusion rate because of quadriceps weakness limiting ambulation.5This suggests that an initial basal rate of 8 ml/h is too high for many patients when using 0.2% ropivacaine. However, simply decreasing the concentration of local anesthetic may provide insufficient analgesia, as reported in an excellent dose–response study.33A great deal of further research is required to both maximize the benefits of perineural local anesthetic infusion while concurrently minimizing the associated risks. Although the results of this study are the most definitive to date regarding the issue of the relative importance of local anesthetic dose versus  concentration/volume during perineural infusion, these data should be viewed as a reference point to help design future clinical trials.

Until additional data are available, practitioners may want to consider steps that may minimize the risk of falls, including minimizing the dose/mass of local anesthetic; providing limited-volume patient-controlled bolus doses that allow for a decreased basal dose without compromising analgesia in some cases41,42—although not all13; using a knee immobilizer and walker/crutches during ambulation39; and educating physical therapists, nurses, and surgeons of possible continuous peripheral nerve block–induced muscle weakness and necessary fall precautions. Of note, in one study involving continuous posterior lumbar plexus blocks, 42% of patients receiving 0.2% ropivacaine at 8 ml/h (16 mg/h plus 8 mg patient-controlled bolus doses) required a decrease in their basal infusion rate because of quadriceps weakness limiting ambulation2; whereas in this study, not a single subject required a decreased basal infusion rate from the original 12 mg/h (with 4 mg bolus doses) and there was no apparent increase in reported surgical pain. It is somewhat hazardous to compare results from differing studies, and we do so here to simply propose a concept and not test a hypothesis; however, these two investigations were completed by the same investigators in a similar patient population at the same institutions.

Although it is improbable that there is one single optimal local anesthetic dose for all patients, there may be an optimal protocol for administering perineural local anesthetic (e.g. , initial basal rate, bolus dose volume, lock-out duration, and subsequent adjustments). Our task is to propose alternative protocols and prospectively and objectively test the results. This study is a first step in this endeavor. Future research should investigate not only the optimal starting dose for various perineural catheter infusions but also the subsequent changes in dosing during the acute postoperative period. Until optimal doses may be accurately and prospectively predicted for each individual patient, it is probable that fixed-rate basal infusions without bolus capability will fail to both optimize postoperative analgesia and minimize muscle weakness (and probably sensory perception and proprioception).

Subjects and nearly all investigators were not masked to treatment group. Yet, it is unlikely that patients had a bias toward one concentration. In addition, endpoint measurements were performed by a physical therapist masked to treatment group assignments. Furthermore, the current finding that only local anesthetic dose and not concentration or volume influences the effects of continuous posterior lumbar plexus blocks may not be applicable to other anatomic catheter locations.29–31 

In summary, for continuous posterior lumbar plexus blocks, local anesthetic concentration and volume do not influence nerve block characteristics. This finding suggests that local anesthetic dose (mass) is the primary determinant of perineural infusion effects.

The authors acknowledge the invaluable assistance of Beverly Morris, R.N., C.N.P., M.B.A., Educator, Department of Nursing, University of California San Diego, San Diego, California; Patrick Olsen, R.N., B.S.N., Nurse Manager, and Claire Hardy, R.N., Assistant Nurse Manager, Hillcrest Hospital, San Diego, California; and the entire Orthopedic Ward staffs at Thornton Hospital, La Jolla, California, and Hillcrest Hospital, San Diego, California.