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Abstract

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgement
  7. Conflict of interest
  8. References

In this controlled, randomized, double-blind study, we compared the pharmacodynamics and pharmacokinetics of ropivacaine and staged injection of lidocaine and ropivacaine in a combined lumbar plexus–sciatic nerve block. The experiment was performed in two parts: pharmacodynamics study (Group r, n = 20; Group lr, n = 20) and pharmacokinetics study (Group R, n = 10; Group LR, n = 10). The sciatic nerve blockade was performed using either (1) 10 mL of 2% lidocaine and then 10 mL of 0.75% ropivacaine (Group lr and Group LR) or (2) 10 mL of normal saline (N.S.) and then 10 mL of 0.75% ropivacaine (Group r and Group R). Two kinds of solutions were ‘staged’ injection. The sensory onset time and sensory recovery time were assessed in the pharmacodynamics study. Arterial blood samples were collected for the pharmacokinetics study. Sciatic sensory block onset times were reduced, and the sensory recovery times were decreased in Group lr. Cmax of ropivacaine in Group LR was significantly higher than that in Group R. A significant increase in AUC(0–t) and AUC(0–∞) was observed in Group LR compared with Group R. When 2% lidocaine and 0.75% ropivacaine are used for a combined sciatic nerve–lumbar plexus block by ‘staged’ injection, lidocaine induced faster onset times, decreased the block duration and increased the AUC and Cmax of ropivacaine.

Lumbar plexus and sciatic nerve blocks have been commonly combined to achieve satisfactory anaesthesia in unilateral lower limb surgery. As the biggest nerve of the body, the onset time of the sciatic nerve block is usually longer than lumbar plexus, requiring additional interventions. Lidocaine with long-acting local anaesthetic mixtures has been combined for nerve blocks, such as the cervical plexus block [1], brachial plexus block [2], femoral and sciatic nerve block [3]. This combination has been demonstrated to produce a faster onset of the sensory blockade, but the effect on the duration of the sensory blockade is controversial [2, 3]. However, there is little literature on safety of the plasma concentration or the pharmacokinetics of this drug combination.

The aim of this controlled, randomized, double-blind study was to verify the pharmacodynamics of lidocaine when combined with ropivacaine in patients undergoing elective knee joint surgery using lumbar plexus and sciatic nerve blocks. The pharmacokinetics of ropivacaine and its equal dose combined with lidocaine by ‘staged’ injection was compared. The sciatic nerve was the nerve of interest for this study.

Methods

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgement
  7. Conflict of interest
  8. References

Materials and equipment

The following is a list of materials and equipment used in this study: 100-mm, 23-gauge insulated stimulating needle (B. Braun, Melsungen, Germany); nerve stimulator (Stimuplex Dig RC, B. Braun, Melsungen, Germany); ropivacaine (AstraZeneca, Sodertalje, Sweden, X980550); and lidocaine (Zhejiang ChengYi Pharmaceutical Company, Wenzhou, China, 20070606).

The high-performance liquid chromatography was performed using an Agilent 1100 series machine (Agilent, Santa Clara, USA). The analytical column was packed with ZORBAX EclipseXDB-C18 (4.6 × 150 mm, 5 μm, Agilent).

Patients

This study was approved by the Ethics Committee at the First Affiliated Hospital of Wenzhou Medical College and Chinese Clinical Trial Registry (Registration number: ChiCTR-ORC-12002099). Sixty patients with ASA physical status I-II (age 18–50 years, weight 50–75 kg) who were scheduled to undergo knee joint surgery with combined lumbar plexus–sciatic nerve blocks were studied. The experiment was performed in two parts: pharmacodynamics study (Group r, n = 20; Group lr, n = 20) and pharmacokinetics study (Group R, n = 10; Group LR, n = 10).

Exclusion criteria included patient refusal, anticoagulant treatment, an allergy to local anaesthetics, neurological or neuromuscular disease, severe liver or renal insufficiency, women of childbearing age and patients unlikely to be fully cooperative during the study, such as those with neurological or psychiatric disorders.

Pharmacodynamics study

Groups

According to a computer-generated sequence of numbers and using a sealed-envelope technique, 40 patients were randomized and assigned to one of two groups: Group r (n = 20), sciatic nerve blockade performed using a solution of 10 mL N.S. and then 10 mL of 0.75% ropivacaine; Group lr (n = 20), sciatic nerve blockade performed using 10 mL of 2% lidocaine and then 10 mL of 0.75% ropivacaine. Two kinds of solutions were ‘staged’ injection. The lumbar plexus blockade was performed using a solution containing 30 mL of 0.5% ropivacaine in both groups.

Anaesthesia methods

In the operating room, patients were monitored (SpO2, electrocardiogram, non-invasive arterial blood pressure), and venous access was obtained and secured. Divided doses of i.v. midazolam (1 mg) and fentanyl (20 μg) were administered when necessary to avoid any anxiety or major discomfort while the block was administered.

An experienced anaesthesiologist performed all blocks with stimulating needles attached to nerve stimulators. The stimulation frequency was set at 1 Hz. The intensity of the stimulating current, initially set to deliver 1.5 mA, was gradually decreased to 0.3 mA while ensuring that the appropriate motor response was maintained. The sciatic nerve location was considered successful if the targeted evoked motor response was plantar flexion or dorsiflexion of the foot. Additionally, the lumbar plexus location was considered successful if the targeted evoked motor response was twitch of rectus femoris or upper displacement of the patella.

Patients were placed in the lateral decubitus position. The leg to be blocked was positioned superior to the other leg and was rolled forward with or without the knee flexed. The lumbar plexus and sciatic nerve block were performed approximately following Winnie's posterior approach [4] and the posterior parasacral approach described by Cuvillon [5]. We used a stimulating needle and a nerve stimulator for the lumbar plexus and sciatic nerve blocks, respectively. The needle was first placed to locate the lumbar plexus and confirmed by stimulation, and then the second needle was placed for the sciatic nerve. The dose of the sciatic block and the lumbar plexus block was injected successively. The two injections were strictly completed within 1.5 min.

Efficacy measurements and variables

Demographic data such as sex, age, ASA status, weight and height were recorded. SpO2, heart rate and arterial blood pressure were measured throughout the entire procedure.

Sensation was assessed every 2 min. for a 60-min. period by an anaesthesiologist blinded to the study solution. The blocks were assessed in the peripheral sensory distribution of lumbar plexus (femoral nerve, saphenous nerve, lateral femoral cutaneous nerve and obturator nerve) (fig. 1) and sciatic nerve (tibial nerve, sural nerve and superficial peroneal nerve). The last needle removal time (from the lumbar plexus) was considered time 0. The sensory onset time was defined as the time elapsed between time 0 and the complete sensory block of all nerve branches (i.e. absence of sensation using a pinprick test). The sensory recovery for the duration of analgesia was defined as the time elapsed between the complete sensory block and the sensory recovery. The patients were confirmed with pinprick testing every 30 min. after operation until sensory recovered completely. If the sensory recovering time was not at the testing time point, patients would call the anaesthesiologist and would be confirmed by pinprick testing. An anaesthesiologist blinded to the study solutions did this job.

image

Figure 1. The peripheral sensory distribution of lumbar plexus and sciatic nerve. The blocks were assessed in the peripheral sensory distribution of lumbar plexus (femoral nerve, saphenous nerve, lateral femoral cutaneous nerve and obturator nerve) and sciatic nerve (tibial nerve, sural nerve and superficial peroneal nerve). The white dots indicate the pinprick test points.

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The block was considered successful if the pinprick sensation was completely lost in the distribution of lumbar plexus and sciatic nerve. A thigh tourniquet was used in all patients during surgery. Pain at the surgical incision or from the tourniquet was noted. When necessary (i.e. pain during the surgery or from the tourniquet), 1 mL of fentanyl and midazolam mixtures (fentanyl 20 μg, midazolam 1 mg) was administered each time. If the mixtures were required more than two times, general anaesthesia was administered to complete surgery. Patients with evidence of epidural spread, as demonstrated by contralateral hip flexor weakness before or after surgery, were recorded.

Pharmacokinetics study

Groups

Twenty patients were randomly assigned to one of two groups: Group R (n = 10) and Group LR (n = 10).

Anaesthesia methods

Block placement and drug administration were the same for the pharmacodynamics study. To avoid the influence of haemodynamics fluctuation and intravenous infusion, an indwelling catheter was placed in the radial artery to monitor the invasive artery blood pressure and collect blood samples.

Sample preparation

Arterial blood samples of 2 mL were obtained immediately after block placement but before administered (zero blank sample) and at 5, 10, 15, 20, 30, 45, 60, 120, 180 and 360 min. after the final injection. Blood was collected in sample tubes with anticoagulant and placed on ice. The plasma was separated by centrifugation (2500 r/min., 15 min.) within 2 hr of collection and stored at −4°C until the drug assay was performed. Lidocaine and ropivacaine were extracted from plasma with acetic ether after alkalization.

Chromatographic conditions

High-performance liquid chromatography was performed with the Agilent 1100 series. The analytical column was packed with ZORBAX EclipseXDB-C18 (4.6 × 150 mm, 5 μm, Agilent). The mobile phase consisted of an acetonitrile–potassium phosphate buffer (0.02 M) (16:84, V/V), and the flow rate was 1 mL/min. The UV detection wavelength was 210 nm, and the internal standard was bupivacaine [6].

Statistical analysis

The number of patients required for the pharmacodynamics study was estimated based on a pilot study of five patients per group in which the sciatic sensory recovery times were 492 ± 112 min. in Group r and 394 ± 79 min. in Group lr. We calculated that we would need to study 18 patients in each group to detect a statistically significant difference in the sensory recovery time between the groups (α = 0.05, β = 0.1). To account for the potential loss of patients in the study, we enrolled 20 patients per group.

Descriptive statistics were used for patient demographics, Cmax, AUC(0–t) and AUC(0–∞), Tmax, t1/2 and Clz/F. Values are reported as the mean ± S.D. Parametric data (age, height and weight), sensory block onset time, total intraoperative IV fentanyl–midazolam and sensory recovery time were analysed with Student's t-test, assuming a normal distribution. The chi-squared test and rank sum test were used to evaluate the differences in gender and surgery duration between groups. Patients' arterial blood drug concentration–time data, along with relevant experimental descriptors, were entered into spreadsheets using the Drug And Statistics Software, version 2.0 (Mathematical Pharmacology Professional Committee of China, Shanghai, China), for the pharmacokinetic analysis [7, 8].

Results

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgement
  7. Conflict of interest
  8. References

Clinical characteristics of volunteers

Sixty patients completed the study protocol: 40 in the pharmacodynamics study and 20 in the pharmacokinetics study. There were no differences in patient characteristics between the groups (table 1).

Table 1. Characteristics of patients in the pharmacodynamics and pharmacokinetics study
 Group r (n = 20)Group lr (n = 20)Group R (n = 10)Group LR (n = 10)
  1. The reported values are mean ± S.D., except for sex and ASA physical status. There were no significant differences between the groups.

Age (years)39 ± 740 ± 938 ± 838 ± 10
Sex (M/F)16/415/57/37/3
Weight (kg)64 ± 1066 ± 862 ± 767 ± 7
Height (cm)168 ± 9168 ± 7164 ± 7168 ± 6
ASA (I/II)16/417/38/27/3
Duration of surgery (min.)78 ± 2674 ± 2378 ± 2975 ± 28

The nerves (lumbar plexus and sciatic) for all patients were localized. No changes in arterial blood pressure, heart rate or SpO2 were observed during the observation period, and no adverse haemodynamic events were reported. No paraesthesias were identified on the operated limb. All blocks were clinically successful. No patient experienced epidural spread or required general anaesthesia. The total intraoperative IV fentanyl–midazolam was not different between the two groups (= 0.146).

Pharmacodynamics

Compared with Group r, the sensory onset time was significantly reduced (10 ± 3 min. versus 24 ± 5 min., < 0.05) (fig. 2), and the sensory recovery duration was shorter (328 ± 91 min. versus 494 ± 109 min., < 0.05) in Group lr for the sciatic nerve (table 2).

Table 2. The onset time and duration of sciatic nerve sensory blockade in the pharmacodynamics study
 Group r (n = 20) Group lr (n = 20)
  1. a

    < 0.05 versus Group r.

  2. The reported values are mean ± S.D.

  3. The last needle removal time (from the lumbar plexus) was considered time 0.

  4. The sensory onset time was defined as the time elapsed between time 0 and the complete sensory block of all nerve branches (i.e. the absence of sensation using a pinprick test). The sensory recovery for the duration of analgesia was defined as the time elapsed between complete sensory block and sensory recovery (the sensory recovery was reported by patients and confirmed by a pinprick test).

Onset time (min.)24 ± 510 ± 3a
Duration (min.)494 ± 109328 ± 91a
image

Figure 2. Kaplan–Meier plot of the sciatic nerve complete sensory block onset time with 10 mL of 2% lidocaine and then 10 mL of 0.75% ropivacaine or 10 mL of normal saline (N.S.) and then 10 mL of 0.75% ropivacaine by a staged injection. The last needle removal time (from the lumbar plexus) was considered time 0. The sensory onset time was defined as the time elapsed between time 0 and the complete sensory block of all nerve branches.

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Pharmacokinetics

High-performance liquid chromatography method

A linear relationship was obtained for the range between 0.05 mg/L and 10 mg/L (r = 0.999). The limit determination of lidocaine and ropivacaine was 0.05 mg/L. The following values are reported for lidocaine and ropivacaine, respectively: the average relative recovery, 99.789 ± 2.936% and 100.318 ± 2.951%; average absolute recovery, 68.357 ± 4.627% and 70.867 ± 4.884%; intraday precision RSD, 0.857 ± 0.425% and 1.364 ± 0.767%; and interday precision RSD, 2.070 ± 1.453% and 1.432 ± 0.226%. The detection method is selective for lidocaine and ropivacaine with no interference from other plasma components.

Pharmacokinetic parameters

Blood samples were collected from 20 patients in the pharmacokinetics study at each time point, yielding a total of 220 plasma samples for analysis. The plasma lidocaine and ropivacaine concentrations for each group are presented in figs 3, 4. The pharmacokinetic parameters of the two groups are presented in table 3. Cmax of ropivacaine was significantly higher (3.1 ± 1.1 mg/L versus 2.6 ± 0.9 mg/L, < 0.05), accompanied by a significant increase of the AUC(0–t) (588 ± 228 mg min./L versus 422 ± 81 mg min./L, < 0.05) and AUC(0–∞) (993 ± 638 mg min./L versus 644 ± 293 mg min./L, < 0.05) in Group LR compared with Group R. No differences in Tmax, t1/2 and Clz/F were found between the two groups (> 0.05).

image

Figure 3. Concentrations of lidocaine measured in individual patients after sciatic nerve injections with 10 mL of 2% lidocaine and then 10 mL of 0.75% ropivacaine (Group LR, n = 10). The lumbar plexus blocks were performed with 30 mL of 0.5% ropivacaine in both groups. Arterial blood samples were obtained immediately before block placement and at 5, 10, 15, 20, 30, 45, 60, 120, 180 and 360 min. after the block placement.

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image

Figure 4. Concentrations of ropivacaine measured in individual patients after sciatic nerve injections with 10 mL of 2% lidocaine and then 10 mL of 0.75% ropivacaine (Group LR, n = 10) or 10 mL of normal saline (N.S.) and then 10 mL of 0.75% ropivacaine (Group R, n = 10). The lumbar plexus blocks were performed with 30 mL of 0.5% ropivacaine in both groups. Arterial blood samples were obtained immediately before block placement and at 5, 10, 15, 20, 30, 45, 60, 120, 180 and 360 min. after the block placement.

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Table 3. Mean pharmacokinetic parameters of lidocaine and ropivacaine in the pharmacokinetics study
Pharmacokinetic parametersRopivacaine in Group R (n = 10)Lidocaine in Group LR (n = 10)Ropivacaine in Group LR (n = 10)
  1. a

    < 0.001 versus Group R.

  2. The reported values are mean ± S.D.

  3. Cmax, peak plasma concentration; Tmax, time to peak; t1/2, distribution of half-life time; AUC(0–t), area under the concentration–time curve (0–6 hr); AUC(0–∞), area under the concentration–time curve (0–∞); CLz/F, apparent clearance.

Cmax (mg/L)2.6 ± 0.92.0 ± 0.53.1 ± 1.1a
Tmax (min.)20 ± 1522 ± 1422 ± 12
t1/2z (min.)223 ± 169151 ± 51264 ± 154
AUC(0–t) (mg min./L)422 ± 81259 ± 80588 ± 228a
AUC(0–∞) (mg min./L)644 ± 293317 ± 123993 ± 638a
CLz/F (L/min./kg)0.009 ± 0.0040.014 ± 0.0050.006 ± 0.004

Discussion

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgement
  7. Conflict of interest
  8. References

Our study demonstrated that 0.375% ropivacaine, when used for sciatic nerve blocks, may require approximately 24 min. to achieve complete sensory anaesthesia. The addition of lidocaine significantly reduced local anaesthetic onset times for the combined block. However, the duration of analgesia was shorter than a long-acting local anaesthetic alone. Compared with the pharmacokinetic parameter of two groups, lidocaine increases the AUC and Cmax of ropivacaine in Group LR.

From our prior experience, we found that the onset of sensory anaesthesia of 30 mL of 0.5% ropivacaine is satisfactory when used for lumbar plexus blockade; therefore, lidocaine was not added. To examine the vasoconstrictive effect of ropivacaine, all local anaesthetic solutions were prepared without epinephrine to reduce absorption. Cuvillon et al. reported the pharmacodynamics and pharmacokinetics of 0.75% ropivacaine (300 mg) and a mixture of 0.75% ropivacaine 20 mL (150 mg) with 2% lidocaine (400 mg) for femoral and sciatic nerve blocks[3]. Because the dose and the concentration of ropivacaine in the mixtures were reduced by the equal volume of lidocaine, it is difficult to compare the pharmacodynamics and pharmacokinetics of these two groups. In our study, 0.75% ropivacaine in the single-use group was diluted by an equal volume of physiological saline, the same volume of 2% lidocaine used in the combined group. The absorption of local anaesthetic is irregular and does not fit an exponential model. Therefore, we chose a non-compartmental analysis to compute the pharmacokinetic parameters, similar to other studies [8, 9].

Our results showed that the long-acting local anaesthetics and lidocaine combined by ‘staged’ injection induced blocks with faster onsets and decreased durations. Our finding was consistent with the research of Cuvillon et al. [3], which compared the pharmacodynamics and pharmacokinetics of bupivacaine, ropivacaine and their equal volume mixtures with lidocaine for femoral and sciatic nerve blocks. In our study, the values for Cmax values in both groups were ropivacaine 3.1 ± 1.1 mg/L and 2.6 ± 0.9 mg/L, lidocaine 2.0 ± 0.5 mg/L, despite the large doses of lidocaine and ropivacaine that were used. No patient experienced local anaesthetic toxicity. The highest concentration of ropivacaine was 4.04 mg/L. Although ropivacaine is less toxic than bupivacaine, local anaesthetic toxicity is possible when the plasma concentration is increased [10-12]. In our study, lidocaine increased the AUC and Cmax of ropivacaine. Perhaps, the main reason is vasodilative effect of lidocaine weakens the vasoconstrictive effect of ropivacaine. So, the blood absorption of ropivacaine increased, and the amount of drug around the nerves decreased. These resulted in the Cmax and AUC of ropivacaine increased and the block durations decreased. Another reason is that metabolism of ropivacaine in liver was hindered by lidocaine due to competence of cytochrome P450. The lack of significant difference in the Clz/F and t1/2 may be related to the fact that the metabolism of lidocaine and ropivacaine was longer than 360 min., which we observed after the final injection in this study. The Tmax of lidocaine (22 ± 14 min.) and ropivacaine (22 ± 12 min.) in Group LR is similar, and the toxicity of local anaesthetics is additive. So, the possibility of local anaesthetic toxicity should be observed closely.

A limitation of this study was that the metabolites of lidocaine and ropivacaine were not examined. The pharmacodynamics and pharmacokinetics results of the sciatic nerve blockade were confounded by an additional lumbar plexus blockade with 30 mL of 0.5% ropivacaine. Furthermore, the number of patients in this study was inadequate to assess the safety of the combination of lidocaine and ropivacaine. A larger study is required to demonstrate whether this combination provides a safety benefit.

The results of this study demonstrate that when 2% lidocaine and then 0.75% ropivacaine are both used in a combined sciatic nerve–lumbar plexus block by ‘staged’ injection, lidocaine induced blocks with faster onset times and decreased durations. Lidocaine increased the AUC and Cmax of ropivacaine, but Tmax, Clz/F and T1/2 were not significantly different. We suggest that when both drugs are used for a combined sciatic nerve–lumbar plexus block, the total anaesthetic dosage should be restricted.

Acknowledgement

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgement
  7. Conflict of interest
  8. References

This work was supported by Department of Science and Technology of Wenzhou (No. Y20090133, No. H20090013). This study was approved by the Ethics Committee at the First Affiliated Hospital of Wenzhou Medical College and Chinese Clinical Trial Registry. Available at: http://www.chictr.org. Registration number: ChiCTR-ORC-12002099.

References

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgement
  7. Conflict of interest
  8. References
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