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Locoregional anaesthesia

The effect of ropivacaine concentration on common peroneal nerve block duration using a fixed dose

A randomised, double-blind trial in healthy volunteers

Christiansen, Claus Behrend; Madsen, Mikkel Herold; Mølleskov, Elise; Rothe, Christian; Lundstrøm, Lars Hyldborg; Lange, Kai H.W.

Author Information
European Journal of Anaesthesiology: April 2020 - Volume 37 - Issue 4 - p 316-322
doi: 10.1097/EJA.0000000000001112

Abstract

Introduction

In peripheral regional anaesthesia the use of diluted local anaesthetic agents has become increasingly popular to reduce the risk of undesirable effects. However, it is unclear whether local anaesthetic dilution shortens the nerve block duration.1–6

To investigate the effect of local anaesthetic concentration on block duration, local anaesthetic dose must be held constant. It is well known that by increasing local anaesthetic dose, either by increasing volume using a constant concentration or by increasing concentration using a constant volume, nerve blocks are prolonged.7,8 It also seems evident that the dose-duration effect becomes progressively smaller with increasing dose, reaching a level above which there is no further block prolongation.3,7–9

Previous concentration-duration trials using fixed local anaesthetic doses have not been able to find differences in nerve block durations between groups.1,2,6 However, these studies did not address the dose-duration ceiling effect and used local anaesthetic doses which were most probably above the ceiling level. Because local anaesthetic dose is a major determinant of block duration, the effect of changing concentration may therefore have been overlooked. Recently, the dose-duration curve of the blockade of the common peroneal nerve was thoroughly described, and a ceiling level of 20 mg of ropivacaine was observed.9 Intentionally choosing a local anaesthetic dose that is lower than the ceiling level, and on the steep part of the dose-duration curve, allows us to investigate the real effect of changing local anaesthetic contration on nerve block duration.

We investigated the effect of five different local anaesthetic concentrations on the duration of the common peroneal nerve block using 10 mg of ropivacaine. Our primary hypothesis was that changing local anaesthetic concentration would affect sensory nerve block duration.

Methods

Before enrolment, approvals were given by the Danish Health and Medicines Authority, the Scientific Ethical Committee of the Capital Region of Denmark (file no. H-17022555; date of approval: 3rd of October 2017), the Danish Data Protection Agency (file no. 2012-58-0004), and The Good Clinical Practice Unit at Copenhagen University Hospitals monitored the trial. Written informed consent was obtained before inclusion of each volunteer. Prior to inclusion of the first volunteer, the trial was registered at the European Union Clinical Trials Register, EU-CTR (Identifier: 2017-003056-23; principle investigator: Claus B. Christiansen, date of registration: 9 August 2017) and at ClinicalTrials.gov (Identifier: NCT03326609). The trial design follows the design of our previous dose-duration trial.9

Volunteers were recruited by a member of the investigator team through advertising in the national Danish website for trial volunteers (https://www.sundhed.dk) from November 2017 until January 2018, by which time all planned participants had completed the trial. Inclusion criteria were: age at least 18 years and ASA Physical Status Class I or II. Exclusion criteria were: allergy to local anaesthetic; BMI of 18 kg m−2 or less; peripheral nerve disease or injury; pregnancy or breastfeeding; habitual use of analgesics, and anatomy preventing successful peripheral nerve catheter insertion. Participants received 1000 DKK (€ 135) in compensation for their participation.

We performed a single-centre, randomised, double-blind trial with five parallel groups. Participants were randomised to receive ropivacaine concentrations of 4, 2, 1, 0.67 or 0.5 mg ml−1. Consequently, participants received 10 mg of ropivacaine dissolved in either 2.5, 5, 10, 15 or 20 ml of 0.9% saline.

One assistant not involved in other parts of the trial produced a random computer-generated allocation sequence (www.sealedenvelope.com) in one block of 60 with a fixed 1 : 1 : 1 : 1 : 1 allocation ratio. Until trial termination, the allocation sequence was concealed from the investigator team and stored both electronically and physically at the Department of Anaesthesiology, Nordsjællands Hospital. The same assistant who produced the randomisation list also produced sealed and opaque envelopes, labelled with the corresponding participant trial number and ordered consecutively from 1 to 60. Each envelope contained a note stating the concentration of local anaesthetic to be infused. Envelopes were stored in a locked room at the Clinical Research Unit, Nordsjællands Hospital. On study days, following local anaesthetic administration procedures, envelopes were resealed and marked with the given date and initials of the involved project nurses responsible for local anaesthetic administration.

Trial interventions and data collection were carried out at the Clinical Research Unit, Nordsjællands Hospital. After baseline tests of sensory and motor function, a peripheral intravenous catheter was inserted. Participants were placed in the prone position and monitored with continuous pulse oximetry. The peripheral nerve catheter insertion site was prepared with chlorhexidine 0.5% and sterile drapes. The transducer was dressed in a sterile probe cover (polyurethane soft flex probe cover kit; Premier Guard, LLC, Houston, Texas, USA). After skin infiltration with 1 ml mepivacaine 20 mg ml−1 + epinephrine 5 μg ml−1 (Carbocain-Adrenalin; AstraZeneca A/S, Copenhagen, Denmark) using a 22-gauge hypodermic needle (Sterican 1/4′; B. Braun, Melsungen, Germany), we inserted a suture-method single orifice peripheral nerve catheter (Certa Catheter, radius of curvature 50 mm, length of needle 100 mm, Ferrosan Medical Devices Sp. z o.o., ul. Koksowa 3, 70-031 Szczecin, Poland) close to the common peroneal nerve shortly after the sciatic nerve bifurcation in the popliteal fossa of the nondominant leg. The peripheral nerve catheters were placed by one of two investigators (CBC or MHM) in short axis using a needle-in-plane, lateral-to-medial ultrasound guided technique (Flex Focus 500 System, transducer 8870; BK Medical, Herlev, Denmark). The needle was advanced just below or above the nerve and then beyond the nerve to exit the skin. 0.9% saline was administered for hydro-dissection and to confirm perineural placement. Placement of the catheter delivery orifice was achieved by dynamic, in-plane visualisation of the catheter and its built-in echogenic markings in addition to intermittent injections of 0.9% saline through the catheter. Placement of the catheter was adjusted until an injection resulted in perineural spread.10–12 A maximum of 5 ml of 0.9% saline was used for the entire catheter insertion procedure. Procedures were recorded for later reference (Epiphan Systems Inc, Palo Alto, California, USA) (Supplemental Digital Content videos 1, https://links.lww.com/EJA/A229; 4, https://links.lww.com/EJA/A230; 7, https://links.lww.com/EJA/A231; 10, https://links.lww.com/EJA/A232; 13, https://links.lww.com/EJA/A233, for examples of a catheter insertion procedures, one participant from each intervention group). After catheter insertion, participants stayed in the prone position until the injected saline had been absorbed from the perineural space. Absorption was confirmed by ultrasound imaging and recorded for later reference (Supplemental Digital Content 2, https://links.lww.com/EJA/A234; 5, https://links.lww.com/EJA/A235; 8, https://links.lww.com/EJA/A236; 11, https://links.lww.com/EJA/A237; 14, https://links.lww.com/EJA/A238, for examples of absorption verifications, one from each intervention group).

A project nurse administered the solution of ropivacaine that was to be infused. The nurse drew up the ropivacaine (Ropivacaine ‘Fresenius Kabi’; Fresenius Kabi, Bad Homburg vor der Höhe, Germany) and 0.9% saline (Natriumklorid ‘Fresenius Kabi’ 9 mg ml−1; Fresenius Kabi) into a syringe (Omnifix 50 ml Luer Lock; B. Braun; Table 1). The syringe was connected to an infusion tube (Injectomat Line, Length 150 cm, Tubing 1.5 × 2.7 mm, Art. no. 9004242, Fresenius Kabi) and a filter (Perifix filter 0.2 μm, B Braun Medical A/S, DK-2000 Frederiksberg, Denmark). The nurse primed the infusion tube and filter with ropivacaine of the allocated concentration before connecting the syringe to an electronic infusion pump (Perfusor Space; B Braun Medical A/S). Finally, the infusion tube and filter were attached to the peripheral nerve catheter. Infusions were administered using a constant infusion rate of 10 ml min−1. An independent observer accompanied the project nurse and verified that infusions complied with the trial protocol and the note stating the concentration of local anaesthetic that was to be infused. Participants and outcome assessors were blinded to infusion procedures. To ensure blinding during local anaesthetic infusions, outcome assessors were not in the room, and infusion pumps were turned away from the participants.

T1
Table 1:
Solutions of ropivacaine used

Trial outcomes

The primary outcome was duration of sensory block defined as altered or no sensitivity to a cold stimulus. A round, cooled glass vial was applied to the lateral part of the lower leg using the contralateral leg as reference. The cooled glass vial was stored in a refrigerator (5° C) until testing. We graded sensory blocks from 1 to 4: 1 similar to the contralateral lower leg, 2 different from the contralateral lower leg, 3 warm sensation or 4 no sensation (i.e. anaesthesia). The grades 2 to 4 were considered to be an active sensory blocks and the presence or abscence of a grade 2 block was used for both the onset and offset times of the sensory block. Testing began 10 min after the end of local anaesthetic infusion and was repeated every 5 min until active sensory block was observed. Thereafter, we performed tests every hour until return of normal cold sensation (cold sensation grade 1).

The secondary outcome was duration of motor block. The strength of foot dorsiflexion was tested with participants in the upright position and graded using a scoring system ranging from 1 to 3: 1 normal strength, 2 paresis or 3 paralysis. Assessments of motor block always accompanied tests of sensory block.

To test whether increasing local anaesthetic volume (local anaesthetic dilution) resulted in increased neural exposure to local anaesthetic, ultrasound scans in the longitudinal axis of the common peroneal nerve were performed. The spread of local anaesthetic was measured in millimetres, from the most proximal to the most distal point at which local anaesthetic was observed in the perineural space. The cutaneous projections of these two points were marked, and the distance between these two projections on the skin was measured. Measurements were agreed upon by two members of the investigator team, and the ultrasound scans were recorded for later reference (Supplemental Digital Content, 3, https://links.lww.com/EJA/A239; 6, https://links.lww.com/EJA/A240; 9, https://links.lww.com/EJA/A241; 12, https://links.lww.com/EJA/A242; 15, https://links.lww.com/EJA/A243, for examples of ultrasound scans of the longitudinal local anaesthetic spread, one from each intervention group).

Explorative outcomes were onset times and degrees of sensory and motor block. Sensory and motor block onset times were categorised as onset time within 10 min (yes/no). Degree of sensory block was categorised as the presence of anaesthesia (yes/no). Participants were also categorised as those without motor block, those with paresis only (motor block grade 2), and those with paralysis (motor block grade 3).

All outcomes were assessed by a member of the investigator team. For exploration of adverse events, a member of the investigator team (EM) made posttrial calls 2 weeks after the study day. The most common adverse events were explored in detail: infection at the catheter insertion sites (pain, redness, swelling) and signs of neural injury (paraesthesia in the innervation area of the common peroneal nerve).

Statistical analysis

For the statistical analyses, we used SPSS Software Package (IBM SPSS Statistics, Version 22.0.0, IBM Corporation, Armonk, New York, USA). Data were categorised and summarised using descriptive statistics. Following tests for normal distribution using visual examination of histograms, normal QQ-plots, and the Shapiro and Wilk test, statistical analyses of the effect of local anaesthetic concentration (categorical ordinal variable) on sensory and motor block duration (continuous variables) were done using one-way Analysis of variance (ANOVA). Analyses of the duration of motor block (paresis and/or paralysis of foot dorsiflexion) and the duration of cold sensation grade 4 (anaesthesia) only included participants with these block characteristics. In case of a significant P value in the one-way ANOVA, we performed univariate regression analysis to elucidate the direction of the effect of local anaesthetic concentration on nerve block duration. The regression analyses were performed using the intervention group who received 0.5 mg ml−1 (20 ml) of local anaesthetic as reference.

Proportional intergroup differences were analysed using the χ2 test. If the χ2 test showed a significant intergroup difference, we performed post hoc pairwise comparisons using Fisher's exact test. Due to multiple pairwise comparisons when using the Fisher's exact test, and to correct for the increased risk of a type I error, we corrected P values using the Bonferroni method [5 × (5 − 1)/2 = 10].

We hypothesised that local anaesthetic concentration would affect sensory nerve block duration. For the power calculation, we used a power calculator for a superiority trial with continuous outcomes at www.sealedenvelope.com. The minimal relevant difference in sensory block duration was set at 3 h. Mean ± SD sensory block duration for 5 ml of ropivacaine 2 mg ml−1 was assumed to be 14 ± 2.5 h.7,13,14 We estimated the dropout rate to be one subject per trial group. With a significance level of 5% and a power of 80%, 60 participants were needed for the entire trial, 12 participants per intervention group.

Results

All participants, who were randomised and received their intended intervention, completed the trial and were analysed for the primary outcome, as depicted in the CONSORT flow diagram (Fig. 1). Participant data are presented in Table 2. One subject was excluded from data analysis of motor block duration due to misunderstanding of the test. The subject kept reporting paresis of foot dorsiflexion despite complete remission of sensory nerve block. The subject later told outcome assessors that the feeling of paresis was caused by pain from the catheter insertion site in the popliteal region. After 1 g of paracetamol, the pain disappeared and so did the feeling of paresis. No adverse events were recorded.

F1
Fig. 1:
CONSORT flow diagram.
T2
Table 2:
Participant data presented as mean ± SD or as number (n)

Trial outcomes are presented in Table 3. All 60 participants had sensory block of the common peroneal nerve, and 56 out of 60 had motor block. Outcome variables were normally distributed. There were no significant differences in mean sensory nerve block durations between groups (P = 0.073). The mean motor nerve block durations differed significantly between the groups (P = 0.002). The subsequent regression analysis demonstrated a reduction in motor block duration with decreasing local anaesthetic concentration (Table 4).

T3
Table 3:
Primary, secondary and explorative outcomes
T4
Table 4:
Regression analyses of motor block duration and duration of anaesthesia

Sensory and motor block onset times were similar between groups (sensory onset time: P = 1.00; motor onset time: P = 0.276). There were no intergroup differences in the proportion of participants reporting cold sensation grade 3 as the highest achieved (P = 0.201). However, although not reaching statistical significance, the proportion of participants with anaesthesia decreased from 11 out of 12 in the highest concentration group to 7 out of 12 in the lowest concentration group (cold sensation grade 4 = no sensation, P = 0.202). Moreover, the duration of anaesthesia was different between groups (cold sensation grade 4 = no sensation, P = 0.009). The subsequent regression analysis demonstrated a shorter anaesthesia duration when decreasing LA concentration (Table 4).

The proportion of participants with paresis (motor block grade 2) and paralysis (motor block grade 3) decreased significantly with local anaesthetic dilution (P = 0.001, adjusted P value). Because of the decreased number of participants with paralysis in the intervention groups receiving diluted local anaesthetic, we did not perform one-way ANOVA for the duration of paralysis. The mean neural exposure to local anaesthetic was significantly different between groups (P = 0.002). The following regression analysis confirmed that mean neural exposure to local anaesthetic was increased with local anaesthetic dilution, and thus with local anaesthetic volume (Table 4).

Discussion

The purpose of this trial was to explore the effects of five different local anaesthetic concentrations on common peroneal nerve block duration. In contrast to our hypothesis, we found that local anaesthetic concentration did not significantly affect sensory block duration. Reducing the local anaesthetic concentration did however shorten the motor block duration, anaesthesia duration and reduced the proportion of participants with paralysis.

Our results support the findings by Nakamura et al.4 using rat sciatic nerves to investigate the effects of lidocaine concentration on nerve block duration. The investigators found increased block durations with increased local anaesthetic concentrations. Likewise, Fenten et al.3 found a dose of mepivacaine above which the effect on the duration of axillary brachial plexus block diminished. They also found a positive effect of mepivacaine concentration on nerve block duration. In contrast, Cappelleri et al2 found equally lasting sciatic nerve blocks with two concentrations of 240 mg of mepivacaine. Based on the results from the study by Fenten et al., this dose is just at the proposed ceiling level. However, they used nerve-stimulation to target the sciatic nerve. Ultrasound guidance would have allowed for a more precise local anaesthetic deposition.15,16 Patients underwent foot surgery and were instructed to activate a catheter-based bolus of local anaesthetic when pain emerged. As pain in the foot may arise from nociceptive stimuli of the saphenous nerve, the risk of observational bias was present.

Our trial was designed to eliminate the above-mentioned limiting factors and to investigate the concentration-duration relationship over a wide range of local anaesthetic concentrations. We used healthy volunteers and a catheter-based technique to optimise blinding of both participants and investigators, and to ensure a constant local anaesthetic infusion rate. We investigated the common peroneal nerve due to its well defined cutaneous innervation area and because it alone innervates the muscles responsible for foot dorsiflexion. We chose our interventional local anaesthetic dose based on a previous investigation of the local anaesthetic volume and dose-duration relationship using 5 to 40 mg of ropivacaine 2 mg ml−1 also in the common peroneal nerve in healthy volunteers.9 This trial showed an increase in nerve block duration when increasing local anaesthetic dose from 5 to 10 mg and again from 10 to 20 mg, but not from 20 to 40 mg. Therefore, we assumed, that if local anaesthetic concentration were to have any effect on block duration, the ropivacaine dose of 10 mg would be enough to provide a sufficient nerve block, but at a level at which block duration was able to change. We used the same five volumes of local anaesthetic as in the aforementioned trial to enable a comparison of the results. Therefore, we did not decide on the interventional local anaesthetic concentrations per se. The local anaesthetic concentrations used in this trial are low if the peripheral nerve blocks alone were to be used for surgical anaesthesia. However, peripheral nerve blocks are increasingly being used for postoperative pain management, and in this regard, long-acting local anaesthetics in low concentrations are indeed clinically relevant.

Based on the combination of observations from the present trial and the trial describing the dose-duration curve in a similar trial design, we propose that the local anaesthetic dose is the primary determinant of nerve block duration. Second, we propose that the sensory nerve block duration is less sensitive to changes in local anaesthetic concentration compared with the motor nerve block duration. Thirdly, local anaesthetic volume per se seems to have no effect on either sensory or motor block duration when investigating this single, peripheral nerve in this range of local anaesthetic solutions. However, our proposals need confirmation based on a third investigation of increasing local anaesthetic concentration with a fixed local anaesthetic volume.

Although investigating healthy, young volunteers is a strength in this trial, it also has its inherent limitations as nerve block duration may increase with age.17 Therefore, our results might have differed if we had investigated an older cohort. Furthermore, insensitivity to a cold stimulus is not the same as analgesia, and the assessment of motor block by a subjective rating scale, also lacks objectivity. One could speculate that if the investigators had stayed in the intervention room and continuously adjusted the catheter delivery orifice during the local anaesthetic infusions or used a straight needle also with the possibility of continuous readjustments during the local anaesthetic infusions, the deposition of local anaesthetic to the nerve would have been more precise. However, we prioritised blinding of all investigators. Furthermore, as neural exposure to local anaesthetic increased with increasing local anaesthetic volume, we consider our technique to be adequate for the deposition of local anaesthetic close to the nerve.

Our findings suggest that injections of diluted local anaesthetic solutions with equal local anaesthetic doses reduce the motor block duration and the incidence of paralysis without compromising the success rate or the duration of sensory block. However, although not statistically significant and below our minimal relevant difference of 3 h, the sensory nerve block duration decreased with local anaesthetic dilution from a mean of 13 h to a mean of 11 h. Also, it should be noted that despite not reaching statistical significance, the proportion of participants with anaesthesia decreased from 11 out of 12 to seven out of 12, and the duration of anaesthesia was also reduced. However, a weakness of our study was testing only hourly. With such testing, changes in block intensity between the measurement times could not be detected. We powered our investigation to explore changes within a minimal relevant time difference of three hours, thus hourly measurements were thought of as adequate. Nevertheless, this implies that the durations anaesthesia could be up to two hours longer than reported, but not shorter. Although we preferred being conservative in the reporting of our results, this is a limitation to our trial.

Sensory onset times were similar between groups. The first measurement was 10 min after the end of local anaesthetic injection. Intergroup differences in onset times smaller than 10 min could therefore not be detected in the current study.

We expect that if we had lowered the local anaesthetic concentration even more, the sensory block duration would have shortened significantly. Conversely, had we used higher concentrations of local anaesthetic, a further prolongation of the motor block is likely. We propose that the concentration-duration patterns of these two block modalities are similar but parallel-shifted so that the steep part of the concentration-duration curve of the sensory nerve block is found at a lower local anaesthetic concentration level compared with that of the motor block.

In conclusion, we found no significant changes in mean sensory block duration over a range of five different local anaesthetic concentrations using a fixed dose of ropivacaine 10 mg. In contrast, local anaesthetic dilution resulted in reduced motor block duration. This knowledge may be important in the postoperative setting in which early mobilisation is essential.

Acknowledgements relating to this article

Assistance with the study: none.

Financial support and sponsorship: this trial was funded by Innovation Fund Denmark and Nordsjællands Hospital.

Conflicts of interest: none.

Presentation: presented in part at the 2018 World Congress on Regional Anaesthesia & Pain Medicine, New York, USA, April 2018.

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