Several factors affect the success of peripheral nerve blocks. Number of injections,1–4 the use of ultrasound,5,6 as well as anatomical aspects such as the site of injection7–9 are elements that increase the success rate, reduce the onset time of local anesthetic (LA), and reduce the volume required for successful peripheral nerve blocks. The pharmacodynamics of LA (volume/concentration ratio) is another important factor in regional anesthesia, but its role in success rate, onset time, and duration of peripheral nerve blocks remains controversial. Pharmacodynamics may be dependent on the technique used and the injection site. For example, it has been suggested that LA volume is the main determinant of efficacy for single-injection axillary block,10 while a high concentration solution seems to be more effective when a single-injection technique is used for Labat’s sciatic nerve block.11,12 Instead, when a multiple injection axillary block is performed, the total dose of LA seems to be the only determinant of the onset time and success rate.13
In this prospective, randomized, single-blinded study, we investigated whether keeping a fixed total dose of LA but different concentrations of mepivacaine solution influenced the onset time and duration of sciatic nerve block when a double-injection Labat’s approach was used.
The study protocol was approved by the local ethics committee (Istituto Ortopedico Gaetano Pini, Milan), and prospectively registered at European Clinical Trials Database (EudraCT number 2013-004633-32). Ninety ASA physical status I to II patients, 18 years old or older, scheduled for foot surgery with major osteotomies and continuous sciatic nerve block were included in the study. Patients were assessed for eligibility during the preoperative screening visit and, after having informed them of the study, written informed consent was obtained from each participant. Patients with clinically significant coagulopathy (hemophilia, von Willebrand disease), infection at the injection site, allergy to LAs, diabetes, or other neuropathies, as well as those receiving opioids for chronic analgesic therapy, were excluded.
Standard monitoring was applied throughout the procedure, including noninvasive arterial blood pressure, electrocardiography (lead II), heart rate, and pulse oximetry. After an 18-gauge IV catheter was inserted in the opposite forearm, all patients received IV premedication with midazolam (0.05 mg/kg). Using a computer-generated sequence of random numbers and a sealed envelope technique, patients were randomly allocated to receive a sciatic nerve block with 12 mL mepivacaine 2% (group I = 45 patients) or with 24 mL mepivacaine 1% (group II = 45 patients).
Regional anesthesia was performed with patients in the lateral decubitus position with the leg to be blocked uppermost. By using the classic Labat approach to the sciatic nerve, an experienced anesthesiologist (GC) skilled in regional anesthesia performed all blocks, targeting each component of the sciatic nerve (peroneal and tibial).
With the aid of a nerve stimulator initially set at 2 Hz, 0.1 millisecond, 1 mA (Plexigon, Vygon, France) a 22-gauge short-beveled 120 mm, stimulating needle (Locoplex,Vygon, France) was inserted perpendicular to the skin until a sciatic motor response was elicited. Plantar-flexion or inversion of the foot and/or flexion of the toes were considered proper motor response for the tibial nerve, while dorsi-flexion or eversion of the foot and/or dorsi-flexion of the toes were considered a proper motor response for the common peroneal nerve. The intensity of the stimulation was gradually decreased maintaining a final current output between 0.35 and 0.40 mA. After the 2 components of the sciatic nerve were identified (tibial and peroneal) a half dose of LA was injected (6 mL in group I, and 12 mL in group II) in each component. The total amount of LA injected was 240 mg in both groups corresponding to the 95% effective dose (ED 95) of mepivacaine 1.5% required to block the sciatic nerve, as it was calculated in a previous study where a single subgluteal injection was performed.7 When necessary, a supplementary ultrasound-guided saphenous nerve block with 10 mL mepivacaine 2% was performed.
Sensory and motor blockade on the operated limb was evaluated every 2 minutes after LA injection for 30 minutes. Data collection was performed by an observer unaware of anesthetic management, and of group randomization. The time required for the onset of complete motor and sensory block was recorded. Sensory block assessment was evaluated as an absence of sensation to cold and pinprick in the common peroneal and tibial nerve distributions (both dorsal and plantar region of the foot) and classified as follows: 1 = normal sensation within the nerve distribution (no block), 2 = blunted sensation (analgesia), and 3 = absence of sensation (anesthesia). Cold sensation was evaluated by applying ice to the skin, while a pinprick test was performed using a 22-gauge hypodermic needle. Complete sensory block was defined as a complete absence of sensation to cold and pinprick tests in both tibial and peroneal components of the sciatic nerve (score = 3). Motor block was assessed for voluntary motor response by asking the patient to plantar flex (to assess tibial motor block) or dorsi-flex (to assess peroneal motor block) his/her foot/fingers and classified as follows: 1 = normal movement, 2 = decreased movement, and 3 = absence of movement (complete motor block). Readiness for surgery was defined as a complete sensory and motor block in both components of the sciatic nerve.
Onset time was defined as the time from the end of injection of LA to readiness for surgery, while time of performance was the time from the insertion of the needle to the end of LA injection.
At the end of a 30-minute evaluation, all patients received ultrasound-guided popliteal-sciatic catheter insertion. In the prone position using a high-frequency (12–15 MHz) linear array transducer (MyLab25, Esaote, Italy), in a sterile sleeve, the sciatic nerve was identified in a transverse cross-sectional view at the apex of the popliteal fossa. When an optimal image of the sciatic nerve, cephalic to the bifurcation, had been obtained, a 10-cm 18-gauge Tuohy-tip needle (Stimulong sono, Pajunk, Germany) was inserted through the skin wheal in-plane beneath the ultrasound transducer, advancing medially toward the sciatic nerve. At this point, a 22-gauge catheter was inserted and advanced 2 to 3 cm past the needletip. The needle was then withdrawn and the catheter tested using the ultrasound transducer to visualize the spread of 2 mL lidocaine 1% adjacent to the sciatic nerve.
The catheter was then secured with a locking system (Lockit, Portex, Italy) and covered with transparent dressing (Tegaderm, 3M, Italy) allowing for direct visualization of both the insertion site and the catheter.
Patients who did not reach surgical anesthesia 30 minutes after LA injection received a supplemental dose of 10 mL mepivacaine 2% through the sciatic-popliteal catheter and were excluded from the offset phase study. Patients who did have surgical anesthesia 30 minutes after LA injection took part in the second phase of the study protocol.
All patients taking part in the second phase of the study had their sciatic catheter connected to a new, electronic, portable infusion pump (Rythmic, Micrel, Greece). This medical device allows continuous infusion with a first programmable bolus of LA. The pump was set to start perfusion at the patient’s first request with an initial bolus of 30 mL levobupivacaine 0.125% (Chirocaine, Abbott, Ireland). The pump was also set to deliver the same levobupivacaine 0.125% perfusion (basal rate 4 mL/h, patient-controlled bolus 2 mL, 20-minute lockout interval). Patients were taught to wait for motor block resolution and then to activate the electronic pump at the first sign of pain. Block duration was defined as the time between LA injection and activation of the electronic pump by the patient. This time corresponded to the onset of pain and was stored in the pump’s memory.
Patients who were not studied during the offset phase received the same postoperative perfusion, without the initial bolus. In this case, the pump was activated by the anesthesiologist at the end of surgery.
For all patients, postoperative analgesia also included ketorolac 30 mg every 8 hours, and oral opioids (oxycodone 10-mg tablets) as a rescue dose.
Statistical analysis was performed using dedicated software Stata 11.1 (StataCorp LP, College Station, TX).
Our primary end point was to determine whether varying volume and concentration of a fixed dose of mepivacaine influenced the duration of sciatic nerve block. Sample size was calculated considering a 240 minutes expected baseline offset time. With a predicted SD = 40 minutes and to observe a difference of at least 30 minutes in block offset time between groups with a 2-tailed α error = 0.05, and power 90%, 38 patients per group would be needed. By considering eventual dislodgement of the sciatic nerve catheter, the sample size was increased to 7 patients per group to account for possible dropouts.
Categorical variables were expressed as number (percentage) and compared with the χ2 test.
Continuous variables were expressed as median (IQR) and compared with the 2-sample Wilcoxon rank-sum (Mann-Whitney U) test. As a summary measure for the Wilcoxon rank-sum tests, Wilcoxon-Mann-Whitney odds (WMWodds) are reported together with their 95% Wald confidence interval. WMWodds were calculated applying logistic regression, with the binary (dependent) variable being the group, from the relevant AUROC (area under the ROC curve). Confidence intervals were calculated from the standard error (SE) of the AUROC.14
Kaplan-Meier curves for block onset and block offset are also reported to show the effect of the study group on these variables. A P value <0.05 was considered statistically significant.
Ninety patients were enrolled at the end of the study, 45 in each group. Forty-four patients in group I and all 45 patients in group II had complete sensory (score = 3) and motor (score = 3) sciatic nerve block 30 minutes after LA injection; the overall success rate was 99%. One patient in group I did not reach complete motor block 30 minutes after LA injection and was excluded from the offset phase study. This patient received a supplemental bolus of 10 mL mepivacaine 2% through his sciatic catheter showing a complete sciatic nerve block 10 minutes later. Two patients (1 in each group) had their sciatic catheter dislodged before block resolution, while another 4 patients (2 in each group) had data regarding their first activation of the electronic pump canceled from the memory. At the end of the randomization, all 90 patients were studied for onset time, while only 83 were also studied for offset (42 patients in group II, 41 in group I).
No difference in demographic characteristics was found between groups (Table 1). Time of performance was shorter in group I, 120 seconds (90–150 seconds), than in group II, 150 seconds (120–180 seconds) (P = 0.0048; WMWodds 2.26 [1.35–4.34]).
The onset time for sensory and motor sciatic nerve block, as well as the onset of pain (block duration) was not statistically different between groups: 4 minutes (2–9 minutes) in group I, and 6 minutes (4–10 minutes) in group II for onset (P = 0.41; WMWodds 1.21 (0.77–1.95)), and 235 minutes (203–250 minutes) in group I, and 240 minutes (218–247 minutes) in group II for offset (P = 0.51; WMWodds 1.20 (0.69–2.16)). Figs. 1 and 2 show the Kaplan-Meier curves for the onset times, and block duration in both groups.
In this prospective, randomized, single-blinded study, we observed that irrespective of concentration of LA solution (2%, or 1%), 240 mg mepivacaine provided successful sciatic nerve block with no difference in the onset times and duration.
Although possible differences in onset times and duration comparable to differences in the performance time between groups cannot be excluded, our results suggest that, when recommended clinical doses are used, the primary determinant of LA characteristics might be the total mass of drug.
By contrast, in a previous comparison between a fixed dose of 1.5% vs 1% of mepivacaine for Labat sciatic nerve block, Taboada et al.11 demonstrated that a higher concentration of LA improved the success rate while shortening the onset time. The authors supported the hypothesis that the size of the sciatic nerve at the gluteal level (1.5–2.0 cm), and the thickness of its epineurium may explain the inability of the LA to completely penetrate the nerve when a small concentration is used, while a large concentration around the sciatic nerve increases the concentration gradient, facilitating the diffusion of LA molecules into the nerve, and shortening the onset of nerve block. By following this hypothesis, our comparison between a fixed lower total dose of 2% vs 1% of mepivacaine was to highlight an even greater difference regarding onset time and success rate between our groups. Unfortunately, our results did not confirm this finding. Taboada et al.11 performed regional anesthesia using a single injection on the tibial component of the sciatic nerve, while in our study the mass of LA injected was equally divided on both the peroneal and the tibial components of the sciatic nerve. In both studies, all injections were performed with a final current output between 0.35 and 0.4 mA, meaning that even the likelihood of intraneural injection was similar.15 The difference might have been that the injection of LA separately into each component of the peripheral nerve resulted in better distribution of the anesthetic solution around the nerve, with an improvement in the quality of regional block.1–4 With this distribution of LA, when usual clinical doses are used, the pharmacodynamics become secondary to the regional anesthetic technique.
This finding had been confirmed by a previous randomized comparison where a multiple-injection technique was used for axillary brachial plexus block,13 and more recently in a study where an ultrasound-guided infraclavicular block was performed.16 Both techniques (multiple injection by nerve stimulator and ultrasound) demonstrated many benefits in terms of success rate, volume required and the onset time compared with single injection for peripheral nerve blocks.1–6 These techniques lead to LA directly contacting a larger part of the nerve tissue, reducing the effects of concentration gradient on peripheral nerve blocks.
Another confirmation of the accuracy of our results is the lack of difference in the duration of sciatic nerve block between groups. To our knowledge, this is the first trial that investigated both the onset and duration of peripheral nerve block with the same regional technique. Recently, Fredrickson et al.17 demonstrated a clear association among LA volume, concentration (and dose), and the duration of interscalene block. Unfortunately, the clinical relevance of the shift demonstrated by different concentrations of ropivacaine (0.375% vs 0.750%) might be questioned (10.75 to 13.75 hours). Moreover, the authors used a single-injection technique that, as previously described, does not allow LA distribution around the nerve comparable to those allowed by multiple injections. Despite this finding, a controlled, sequential, up and down study in healthy volunteers suggested a correlation between LA volume and secondary outcome, block duration.18 In this study, the authors showed an ED99 of 0.10 mL/mm2 cross-sectional nerve area for ultrasound-guided sciatic nerve block, equivalent to 5.7 mL mepivacaine 1.5% for a sciatic nerve with a cross-sectional area of 57 mm2. Although higher doses of mepivacaine for successful sciatic nerve block have been reported,2–4,7–9 the 240 mg used in our study might have been too much to highlight the role of a concentration gradient.
Considering our WMWodds results, a limitation of our study is that our sample size was too small to exclude differences in onset and offset times comparable to the differences in performance time between groups.
In conclusion, our prospective, randomized, single-blinded study found no evidence that altering volume and concentration while maintaining a fixed total dose of mepivacaine alters the onset time and duration of sciatic nerve block when a multiple-injection technique was used. Possible differences in onset time and duration comparable to differences in the performance time between groups cannot be excluded.
Our study supports the hypothesis that when the anesthetic solution is used at recommended clinical doses, the total mass of drug might be the main determinant of LA effects during peripheral nerve blocks.
Name: Gianluca Cappelleri, MD.
Contribution: This author helped design the study, conduct the study, and write the manuscript.
Attestation: Gianluca Cappelleri has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.
Name: Andrea Luigi Ambrosoli, MD.
Contribution: This author helped design the study.
Attestation: Andrea Luigi Ambrosoli has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.
Name: Stefania Turconi, MD.
Contribution: This author helped write the manuscript.
Attestation: Stefania Turconi has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.
Name: Marco Gemma, MD.
Contribution: This author helped analyze the data.
Attestation: Marco Gemma has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.
Name: Erika Basso Ricci, MD.
Contribution: This author helped conduct the study.
Attestation: Erika Basso Ricci has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.
Name: Gabriele Cornaggia, MD.
Contribution: This author helped conduct the study and write the manuscript.
Attestation: Gabriele Cornaggia has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.
This manuscript was handled by: Terese T. Horlocker, MD.
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