Anesthesia & Analgesia:
Regional Anesthesia and Pain Management
Pharmacokinetics and Pharmacodynamics of Ropivacaine 2 mg/mL, 5 mg/mL, or 7.5 mg/mL After Ilioinguinal Blockade for Inguinal Hernia Repair in Adults
Wulf, Hinnerk MD*; Worthmann, Frank MD*; Behnke, Hagen MD*; Böhle, Arnd S. MD†
*Departments of Anesthesiology and Critical Care Medicine and †General and Thoracic Surgery, Hospital of the Christian-Albrechts-University, Kiel, Germany
July 29, 1999.
Address correspondence and reprint requests to Prof. Dr. Hinnerk Wulf, Department of Anesthesiology and Critical Care, Christian-Albrechts-University, Schwanenweg 21, D24105 Kiel, Germany. Address e-mail to email@example.com.
The clinical work was performed at the Department of Anesthesiology and Critical Care Medicine and the Department of General and Thoracic Surgery Hospital of the Christian-Albrechts-University, Kiel, Germany. The laboratory for HPLC-analysis of the Department of Anesthesiology and Critical Care Medicine is located at the Institute of Pharmacology of the Christian-Albrechts-University, Kiel, Germany.
The aim of our study was to evaluate the pharmacokinetics and pharmacodynamics of ropivacaine in ilioinguinal-iliohypogastric blocks (IIB). After ethics committee approval and informed consent, 80 male adults scheduled for inguinal hernia repair were enrolled and randomized into four groups. After induction of general anesthesia, an IIB was performed double blinded in Groups 1, 2, and 3 with 0.25 mL/kg ropivacaine 2 mg/mL, 5 mg/mL, or 7.5 mg/mL and with saline in the Control group. Plasma concentration of ropivacaine was determined in venous blood using reversed-phase high-performance liquid chromatography. IIB with ropivacaine resulted in peak plasma concentrations of 0.3 ± 0.15 μg/mL (Group 1) (mean ± SD), 0.75 ± 0.45 μg/mL (Group 2), or 1.57 ± 0.82 μg/mL (Group 3). These concentrations occurred after 30 (15–60) min, median (range), 30 (10–60) min, and 45 (15–60) min, in the respective groups. Three of 19 patients in Group 1, 6 of 18 in Group 2, and 5 of 20 in Group 3 did not need any additional analgesics within 24 h postoperatively, but all 20 control patients did. Time to the first demand for analgesia was significantly shorter in the Control group (median 0.3 h [range 0–2.8]) compared with 1.5 h (0.5–24 h), 2 h (0.5–24 h), and 2 h (1.0–24 h) in Groups 1, 2, and 3, respectively. Three patients in Group 3 had a postoperative motor block of the femoral nerve. In conclusion, a ropivacaine dose of 0.25 mL/kg of 5 mg/mL seems adequate for IIB accompanying general anesthesia for postoperative pain relief. However, the pharmacokinetic results obtained suggest that even larger doses (0.25 mL/kg of 7.5 mg/mL ropivacaine) for IIB do not result in plasma concentrations in a toxic range.
Implications: Ropivacaine, a new local anesthetic, proved to be effective for pain relief after hernia repair in ilioinguinal blocks accompanying general anesthesia. Plasma concentrations peaked after 30–45 min, and were within safe limits after application of 0.25 mL/kg of 2, 5, or 7.5 mg/mL ropivacaine.
Ropivacaine has been shown to be less toxic than racemic bupivacaine in preclinical studies (1–3). Several studies have shown that ropivacaine is a suitable drug for regional anesthesia (4–10). Ilioinguinal-iliohypogastric block (IIB) or iliac crest block (11,12) are very well established methods of providing intra- and postoperative analgesia for inguinal hernia repair. Experience with ropivacaine is limited in peripheral nerve blocks (13–16). We evaluated plasma concentrations (pharmacokinetics) and efficacy (pharmacodynamics) of ropivacaine after IIB in adults using different concentrations of ropivacaine to test the hypothesis that ropivacaine does not lead to plasma concentrations in a toxic range after effective dosage for IIB.
Eighty male adult patients, ASA status I or II, scheduled for elective primary single-sided inguinal hernia repair under general anesthesia were enrolled in this prospective randomized double-blinded study. Hernia repair was performed according to a standardized modified Shouldice-procedure by the same team of surgeons. The biometric data are depicted in Table 1. The study protocol had been approved by our university’s hospital ethical committee and written, informed consent was obtained. After premedication with a benzodiazepine (20 mg dipotassiumchlorazepat), general anesthesia was induced with fentanyl 1 μg/kg and propofol 2–3 mg/kg and a laryngeal mask was placed. For maintenance, isoflurane (0.4–1.2 vol%) in 65% N2O/35% O2 was administered. Patients were randomized by a computer-generated list to receive 0.25 mL/kg body weight of saline (Control) or ropivacaine 2 mg/mL (Group 0.2%), 5 mg/mL (Group 0.5%), or 7.5 mg/mL (Group 0.75%) after induction, but before surgery. The solution (e.g., 20 mL for an 80-kg patient) was injected within 2 min, 3–5 cm medial to the anterior superior iliac spine via a 5-cm atraumatic Sprotte cannula after a “click” phenomenon was observed as a sign of having passed the external oblique fascia. Patients were evaluated postoperatively using pain scores (visual analog score [VAS] 0–100) in 10-min intervals (first hour) and at hourly intervals up to the time of the first demand for analgesia, which was given at a VAS score >30 at rest.
Plasma concentrations of ropivacaine were determined from peripheral venous samples before and 5, 10, 15, 20, 30, 45, 60, and 90 min after the injection. After centrifugation, plasma was stored at –20°C awaiting analysis. A high-performance liquid chromatographic (HPLC) method described previously for the analysis of bupivacaine (17) was modified to determine concentrations of ropivacaine. In short, ropivacaine was extracted from plasma by solid phase extraction (Baker 24 SPE, Waters Sep Pak Cartridge C 18; Waters, Milford, MA). The HPLC device consisted of a gradient pump (Merck-Hitachi L 6200, AS-2000, Merck, Darmstadt, Germany) and a nucleosil-C 18 reversed phase column (LiChrospher 60 RP Select-B, Merck). The absorption was measured at a wavelength of 203 nm (Merck-Hitachi L 4000 UV Detector) and integrated (HPLC-Manager, D-6000 A Interface). The mobile phase, acetonitril/0.1% phosphate buffer (23:77) at pH 2.1, was sent through the column at a flow rate of 1 mL/min. Retention time for ropivacaine was 10 min and the internal standard etidocaine peaked at 14 min. Plasma samples were assayed in duplicate. The coefficient of variation showed acceptable precision of the assay below 5% in the range of 0.02–10 mg/L.
Median, 5, 25, 75, 95 percentiles, range, or mean ± SD are given as indicated. Figure 1 uses box and whiskers plots. A sample size estimation based on a minimum detectable difference in the peak plasma concentrations of 0.5 μg/mL (SD ± 0.5 μg/mL) resulted in a sample size of n = 17 per group. Accordingly, a sample size of n = 19 was calculated to detect a 1/3 improvement in patients without use of analgesics within 24 h postoperatively (5% in the Control group versus 40% in the study group) (GraphPAD, San Diego, CA). Kruskal-Wallis test with Dunn’s multiple comparison test (maximum plasma concentration, time to the first analgesic) and χ2 test (number of patients without additional analgesics) were used for comparison.
Three patients were excluded from further analysis because of incomplete sampling of plasma specimen (one in Group 0.2%, two in Group 0.5%). In the local anesthetic groups, all but one patient (Group 0.2%) had a satisfactory block for surgery indicated by a low concentration of isoflurane required for maintenance of anesthesia (<0.7 vol% expiratory concentration). Perioperatively, no serious adverse events or systemic local anesthetic toxicity because of IIB blocks with ropivacaine were observed. Six patients (one in Group 0.2%, two in Group 0.5%, and three in Group 0.75%) showed sensory block of the femoral nerve postoperatively, three of whom had a motor block (Group 0.75%).
Three of 19 (16%) patients in Group 0.2%, 6 of 18 (33%) in Group 0.5%, and 5 of 20 (25%) in Group 0.75% did not need additional analgesics during the first 24 h after surgery, whereas significantly more patients in the Control group did (20 of 20). The time to the first demand for analgesia was significantly shorter in the Control group (median 0.3 h [range 0–2.8]) compared with the ropivacaine groups: 1.5 h (0.5–24 h), 2 h (0.5–24 h), and 2 h (1.0–24 h) in Group 0.2%, Group 0.5%, and Group 0.75%, respectively (Table 1).
IIB with ropivacaine resulted in peak plasma concentrations of 0.3 ± 0.15 μg/mL (mean ± SD), 0.75 ± 0.45 μg/mL, and 1.57 ± 0.82 μg/mL after administration of 0.25 mL/kg of the 0.2%, 0.5%, or 0.75% solutions, respectively (nonparametric data are presented in Figure 1). Maximum plasma concentrations occurred after 30 (15–60) min, median (range), 30 (10–60) min, and 45 (15–60) min, in the 0.2%, 0.5%, and 0.75% groups, respectively.
The median maximum concentrations in young patients (<30 yr) did not differ from those measured in senior patients (>65 yr): 0.25 (range 0.18–0.39) vs 0.30 (0.20–0.60) μg/mL (Group 0.2%), 0.9 (0.22–1.65) vs 0.61 (0.28–1.98) μg/mL (0.5%), and 1.70 (0.81–2.00) vs 1.44 (1.05–2.82) μg/mL (0.75%).
IIB is an established method of analgesia for inguinal hernia repair in adults and children (11,12,18). This technique can be used to perform hernia repair in local/regional anesthesia in adults or may be combined with general anesthesia to provide postoperative pain relief. Our study emphasizes the latter, because fewer patients with IIB required additional analgesics, an advantage of special interest in day case surgery.
Before this study, ropivacaine had not been evaluated for IIB. Therefore, the optimal concentration (or dose) of ropivacaine for IIB was a secondary study goal. Our study was designed to be sensitive to evaluate differences in effectiveness of the block: all concentrations tested proved to be effective for postoperative pain relief, because the time to the first demand for an analgesic was significantly longer than in the Control group. Our results indicate that under these conditions there are no major differences in postoperative pain prevention comparing identical volumes (on a milligram/kilogram basis) of different commercially available concentrations of ropivacaine (0.2%, 0.5%, and 0.75%). A limitation of this study is that the number of patients included probably was too small to detect a difference of intermediate size among the ropivacaine study groups. Furthermore, we did not test more dilute solutions of ropivacaine and no standard comparator (e.g., lidocaine or bupivacaine) was included. Compared with previous studies using different local anesthetics (19–22), the resulting residual analgesia (median: approximately two hours) with ropivacaine seems to be disappointing at first glance. The following explanation for this discrepancy can be offered: 1) Most reports give means, whereas median values are considerably lower (non-Gaussian distribution, cf. to Table 1). 2) We used preincisional blocks, whereas some of the other investigators performed the block at the end of surgery. 3) In contrast to most other reports, we did IIB exclusively, e.g., without additional local infiltration or field blocks. 4) For our patients, a low cut was set for the application of rescue analgesic (VAS 30). 5) A closer look at previous investigations reveals that bupivacaine for comparison results in a short-lasting analgesic effect as well (one to six hours) (19,21,22).
Peak plasma concentrations as an indicator for potential central nervous system or cardiac toxicity were dose dependent and were highest in the group receiving the strongest concentration (and therefore highest dose) (Group 0.75%). Plasma concentration threshold for toxicity of racemic bupivacaine is stated to be 2–4 mg/L for the total concentration (23). Experience with toxic plasma concentrations of S-ropivacaine in humans is still limited. Based on preclinical in vitro and animal studies one should expect the threshold for toxicity to be less for bupivacaine than for ropivacaine. Scott et al. (24) reported mild central nervous system symptoms at venous plasma concentrations ranging from 1 to 2 mg/L after IV administration of ropivacaine in unpremedicated volunteers. In patients after regional blocks, maximal plasma concentration of 3.70 mg/L (8), 2–3 mg/L (13), and 2.46 mg/L of ropivacaine (9) were observed without adverse reactions. In this study, the highest individual peak plasma concentration after IIB was 3.61 μg/mL, 15 minutes after a dose of 17 mL of ropivacaine 0.75% (=127.5 mg) in a 52-year-old patient. Of course, signs of central nervous system toxicity could have gone unnoticed, because in most cases patients were under general anesthesia at the time of peak plasma concentrations.
In conclusion, if IIB with ropivacaine is to be used in addition to general anesthesia to provide postoperative pain relief, a concentration of 0.5% seems adequate. The pharmacokinetic results obtained for 0.75% ropivacaine suggest that 0.25 mL/kg of these higher concentrations may also be used safely. Nevertheless, in practice, IIB without general anesthesia involve additional field block and further use of local anesthetics, so the total volume used is inevitably larger. Femoral nerve block occurred with ropivacaine 0.75%, whereas this phenomenon was absent in the 0.2% or 0.5% groups. Because femoral nerve motor block might delay mobilization and prolong hospital stay, a 0.75% concentration is probably less suitable for day case surgery.
The assistance of our laboratory technician Margret Betz in the analytical assays of plasma concentrations of ropivacaine is gratefully acknowledged. Thanks are due to the members of the Institute of Pharmacology (chairman Prof. Dr. Thomas Unger) for their hospitality and cooperation and to Dr. Thomas Smith, London, for his critical reading, help, and humor while preparing the English version of this manuscript.
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© 1999 International Anesthesia Research Society