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* From the Department of Anesthesiology, Maisonneuve-Rosemont Hospital;
and the Faculty of Pharmacy, University of Montreal, Montreal, Quebec, Canada.
Address correspondence to: Dr Joanne Guay, Département d’anesthésie-réanimation, Hôpital Maisonneuve-Rosemont, 5415 boul. L’Assomption, Montréal, Québec H1T 2M4, Canada. Phone: 514-252-3426; Fax: 514-252-3542; E-mail: joanne.guay{at}umontreal.ca
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Abstract |
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Methods: Paravertebral blockade was performed using a solution of 10 mL ropivacaine 0.75%, 10 mL lidocaine CO2 2% plus 0.1 mL epinephrine 1:1000 either by a single injection at T3 or T4 (Group S, n = 6) or by five injections of 4 mL each at T2 to T6 (Group M, n = 8). Blood samples were taken at zero, five, ten, 15, 20, 30, 45, 60 and 90 min and at two, three, four, five, six and eight hours. Ropivacaine and lidocaine plasma concentrations were measured by high performance liquid chromatography.
Results: Maximal plasma concentrations were comparable for lidocaine: 2.6 ± 1.3 (S) vs 2.6 ± 0.8 µg•mL-1 (M) and for ropivacaine: 1.3 ± 0.2 (S) vs 1.3 ± 0.1 µg•mL-1 (M). Area under the plasma concentration-time curve was higher in Group M for lidocaine: 577.6 ± 146.1 vs 401.7 ± 53.2 mg•min-1•mL-1 (P = 0.04) but similar for ropivacaine: 381.1 ± 95.4 (M) vs 363.1 ± 85.3 mg•min-1•mL-1 (S).
Conclusions: The injection of a single large bolus of local anesthetics into the paravertebral space does not increase its absorption. Maximal ropivacaine plasma concentrations resulting from paravertebral blockade are similar to those reported with equivalent doses of bupivacaine.
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Introduction |
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Ropivacaine could be a good choice for paravertebral blockade due to its long-lasting action and its low cardiotoxicity.7 Plasma concentrations of ropivacaine resulting from paravertebral blockade have not been reported.
The aims of this study were to determine if the single injection technique of paravertebral blockade could have a greater possibility of inducing toxic plasma concentrations of local anesthetics than the multiple injection technique and to describe ropivacaine plasma concentrations resulting from paravertebral blockade.
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Methods |
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Patients in Group M received five paravertebral injections from levels T2 to T6 inclusively, whereas those from Group S received a single paravertebral injection at T3 or T4. After standard monitoring plus sedation with midazolam (1–3 mg iv) and fentanyl (50–150 µg iv), blocks were performed under sterile condition according to a standard technique of paravertebral blockade.8 A mixture of 10 mL ropivacaine 0.75%, 10 mL lidocaine CO2 2% and 0.1 mL of epinephrine 1:1000 was used. For patients in Group M, 4 mL of the solution were injected at each level. For patients in Group S, 3 mL of the solution were injected initially as a test dose, followed by 17 mL in four successive boluses. In both groups, the third and fourth cervical plexus rami were anesthetized by sc infiltration below the clavicle using an extra 100 mg lidocaine. For the surgery, the attending anesthesiologist could administer supplemental midazolam, fentanyl and/or propofol or resort to general anesthesia with the insertion of a laryngeal mask airway, higher doses of propofol and nitrous oxide if judged necessary.
A venous heparin-lock was installed for blood sampling on the opposite side of the iv. Blood samples of 6 mL were taken to measure the concentrations of ropivacaine and lidocaine at zero, five, ten, 15, 20, 30, 45, 60 and 90 min and at two, three, four, five, six and eight hours following the injection. This allowed for the detection of maximal concentrations (Cmax) even if a second peak appeared at 244 min such as previously described by Kopacz et al. for ropivacaine.2 Samples were placed on ice and centrifuged within one hour. Plasma samples were stored at -20°C until assayed.
Samples were prepared according to the technique reported by Björk et al. (precision of 10%).9 To 1 mL sample of plasma, 5 µg bupivacaine were added as an internal standard, followed by 375 µL sodium carbonate 10% and extracted with 5 mL n-hexane:methylene chloride (4:1, v/v) by gentle agitation for 30 min. After centrifugation, organic layers were transferred to other tubes and evaporated to dryness. Residues were reconstituted with 250 µL mobile phase [70 mM sodium sulfate in 1.25 mM sulphuric acid: ACN 65:35 (v/v)], and analyzed using high performance liquid chromatography (HPLC) separation reported by Arvidsson and Eklund (precision of 10%), with some modifications.10 Aliquots of 100 µL were injected into the analytical column (Hichrom S5 ODS 1) at 40°C of an HPLC system, with UV detection at 210 nm. Calibration curves ranged from 125 to 4000 ng•mL-1 plasma for ropivacaine and from 250 to 8000 ng•mL-1 plasma for lidocaine.
Statistical analysis was performed using a Chi square, Student’s t tests with the Bonferroni correction, one-way or two-way ANOVA for repeated measures where appropriate. A P < 0.05 was considered significant.
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Results |
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). Mean maximal plasma concentrations were comparable between the two groups for lidocaine and ropivacaine (Figures 1 and 2; Tables II and III). Time to achieve maximal plasma concentrations was: 21.7 ± 18.4 min (Group S) vs 20.6 ± 12.1 min (Group M) for lidocaine and: 84.3 ± 35.7 min (Group S) vs 49.4 ± 21.3 min (Group M) for ropivacaine. The area under the plasma concentration-time curve between zero and eight hours was higher in Group M for lidocaine: 577.6 ± 146.1 vs 401.7 ± 53.2 mg•min-1•mL-1 (P = 0.04) but similar for ropivacaine: 381.1 ± 95.4 (Group M) vs 363.1 ± 85.3 mg•min-1•mL-1 (Group S). Local anesthetic concentrations were < 6 µg•mL-1 for lidocaine and < 3 µg•mL-1 for ropivacaine for all patients at all times. No patients demonstrated signs or symptoms compatible with local anesthetic toxicity throughout the study.
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Discussion |
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and III). Though patients with the multiple injection technique tend to have slightly higher early concentrations, this was not statistically nor clinically significant. Indeed, area under the plasma concentration-time curve for lidocaine was even slightly higher in the multiple injection technique group. These results indicate that the injection of a single large bolus of local anesthetic does not increase its absorption and hence will not be prone to induce a higher risk of toxicity. Absorption of local anesthetics is influenced by the site of injection, dosage and volume used, addition of a vasoconstrictive agent and pharmacologic profile of the local anesthetic itself.11 Paravertebral and intercostal blocks are known to induce the highest local anesthetic concentrations while cutaneous infiltrations are less susceptible to lead to high blood concentrations and intoxications. When excessive blood concentrations of local anesthetics are achieved, the central nervous system (CNS) is usually affected first, while direct cardiac toxicity and cardiovascular collapse are associated with higher blood concentrations.11 In the present study, none of the patients had blood levels compatible with CNS or cardiac toxicity since lidocaine concentrations were below 6 µg•mL-1 at all times and ropivacaine concentrations were below 3 µg•mL-1 in all the measurements done. None of the patients studied had clinical signs or symptoms indicative of CNS toxicity at any time. However, though the concentrations of local anesthetics measured were well below known toxic levels, it is important to take into account the fact that, for a mixture of local anesthetics, toxicities of the two agents are usually additive.12 Anesthesiologists often use mixtures of local anesthetics in order to combine desirable properties, for example a rapid onset with lidocaine and long postoperative analgesia with ropivacaine or bupivacaine. There is also hope that maximal plasma concentrations of the two agents will not be achieved at the same time and that this will reduce the risk of inducing toxicity. Indeed, in the present study, maximal plasma concentrations of ropivacaine were achieved while lidocaine plasma concentrations were already decreasing, suggesting that the combination of these two agents for paravertebral blockade may indeed be interesting in terms of diminishing the risks of high blood local anesthetic concentrations.
Ropivacaine has gained wide popularity in the recent years among other anesthetic agents, mostly because of its claimed low cardiotoxicity compared to other long-acting local anesthetics such as bupivacaine.7 Several adverse events have nevertheless been reported, leading most often to isolated CNS toxicity or to CNS toxicity with minor cardiovascular signs such as sinus tachycardia. Severe cardiac dysrythmias have, however, also been reported.13–17 These adverse events were all attributed to the accidental intravascular injection of ropivacaine except for one patient who had repeated intoxication after doses of 6 and 4.5 mg•kg-1 of ropivacaine for brachial plexus blocks.14 Using a two-compartment pharmacokinetic model, Muller et al. estimated that their patient who had grand mal seizure during an injection of ropivacaine for a sciatic block, reached a maximal concentration of 5.75 mg•L-1.16 Though such a value was not observed in the present study, it is a concentration that can easily be achieved at or within 48 hr when ropivacaine is administered as a continuous infusion in an epidural or a plexus block.18,19 However, since continuous infusion of local anesthetics are usually administered after major surgeries, the increase in 
-glycoprotein that normally occurs in these situations may offer a certain degree of protection by lowering free drug concentrations despite raising total blood concentrations of local anesthetics.19
Although comparisons from one study to another are always suboptimal, it seems reasonable to think that maximal concentrations achieved after the injection of ropivacaine into the paravertebral space are similar to those obtained with bupivacaine. Atanassoff et al. reported mean concentrations of bupivacaine of 1.44 ± 0.2 µg•mL-1 after the injection of 80 mg bupivacaine (16 mL bupivacaine 0.5%) while our patients had mean concentrations of 1.3 ± 0.4 µg•mL-1 with 75 mg ropivacaine (10 mL ropivacaine 0.75%).20
The most striking observation though in the present study is the fact that ropivacaine blood levels did not decrease, or very little, during the entire study period. The intrinsic vasoconstrictive properties of ropivacaine itself or the added epinephrine might be responsible for this phenomenon.21 Ropivacaine may have been slowly and steadily liberated into the blood vessels during the entire study period (eight hours). Thus, blood concentrations of ropivacaine never achieved dangerous levels but apparent clearance was slow and blood concentrations were maintained at the same level for several hours.
In conclusion, the single injection technique of paravertebral blockade does not increase local anesthetic absorption. Maximal ropivacaine plasma concentrations resulting from paravertebral blockade are similar to those reported with equivalent doses of bupivacaine.
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Acknowledgments |
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Footnotes |
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Revision received March 3, 2003. Accepted for publication August 21, 2000.
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2 Kopacz DJ, Emanuelsson BM, Thompson GE, Carpenter RL, Stephenson CA. Pharmacokinetics of ropivacaine and bupivacaine for bilateral intercostal blockade in healthy male volunteers. Anesthesiology 1994; 81: 1139–48.[Medline]
3 Moorthy SS, Dierdof SF, Yaw PB. Influence of volume on the spread of local anesthetic-methylene blue solution after injection for intercostal block. Anesth Analg 1992; 75: 389–91.
4 Cheema SPS, Isley D, Richardson J, Sabanathan S. A thermographic study of paravertebral analgesia. Anaesthesia 1995; 50: 118–21.[Medline]
5 Pusch F, Freitag H, Weinstabl C, Obwegeser R, Huber E, Wilding E. Single-injection paravertebral block compared to general anaesthesia in breast surgery. Acta Anaesthesiol Scand 1999; 43: 770–4.[Medline]
6 Terheggen MA, Wille F, Borel Rinkes IH, Ionescu TI, Knape JT. Paravertebral blockade for minor breast surgery. Anesth Analg 2002; 94: 355–9.
7 Mazoit JX, Decaux A, Bouaziz H, Edouard A. Comparative ventricular electrophysiologic effect of racemic bupivacaine, levobupivacaine, and ropivacaine on the isolated rabbit heart. Anesthesiology 2000; 93: 784–92.[Medline]
8 Kopacz DJ, Thompson GE. Celiac and hypogastric plexus, intercostals, interpleural, and peripheral neural blockade of the thorax and abdomen. In: Cousins MJ, Bridenbaugh PO (Eds.). Neural Blockade in Clinical Anesthesia and Management of Pain, 3rd ed. Philadelphia: Lippincott-Raven; 1998: 451–8.
9 Björk M, Pettersson KJ, Osterlof G. Capillary gas chromatographic method for the simultaneous determination of local anaesthetics in plasma samples. J Chromatogr 1990; 533: 229–34.[Medline]
10 Arvidsson T, Eklund E. Determination of free concentration of ropivacaine and bupivacaine in blood plasma by ultrafiltration and coupled-column liquid chromatography. J Chromatogr B Biomed Appl 1995; 668: 91–8.[Medline]
11 Berde CB, Strichartz GR. Local anesthetics. In: Miller RD (ED.). Anesthesia 5th ed. Philadelphia: Churchill Livingstone; 2000: 491–521.
12 Spiegel DA, Dexter F, Warner DS, Baker MT, Todd MM. Central nervous system toxicity of local anesthetic mixtures in the rat. Anesth Analg 1992; 75: 922–8.
13 Petitjeans F, Mion G, Puidupin M, Tourtier JP, Hutson C, Saissy JM. Tachycardia and convulsions induced by accidental intravascular ropivacaine injection during sciatic block. Acta Anaesthesiol Scand 2002; 46: 616–7.[Medline]
14 Ala-Kokko TI, Lopponen A, Alahuhta S. Two instances of central nervous system toxicity in the same patient following repeated ropivacaine-induced brachial plexus block. Acta Anaesthesiol Scand 2000; 44: 623–6.[Medline]
15 Abouleish EI, Elias M, Nelson C. Ropivacaine-induced seizure after extradural anesthesia. Br J Anaesth 1998; 80: 843–4.
16 Muller M, Litz RJ, Huler M, Albrecht DM. Grand mal convulsion and plasma concentrations after intravascular injection of ropivacaine for axillary brachial plexus blockade. Br J Anaesth 2001; 87: 784–7.
17 Ruetsch YA, Fattinger KE, Borgeat A. Ropivacaine-induced convulsions and severe cardiac dysrythmia after sciatic block. Anesthesiology 1999; 90: 1784–6.[Medline]
18 Kaloul I, Guay J, Côté C, Halwagi A, Varin F. Ropivacaine plasma concentrations during continuous lumbar plexus blockade: is there any difference between the three-in-one technique and the posterior (psoas compartment) technique? ASA Meeting 2002; A954 (abstract).
19 Burm AGL, Stienstra R, Brouwer RP, Emanuelsson BM, van Kleef JW. Epidural infusion of ropivacaine for postoperative analgesia after major orthopedic surgery: pharmacokinetic evaluation. Anesthesiology 2000; 93: 395–403.[Medline]
20 Atanassoff PG, Alon E, Weiss BM. Intercostal nerve block for lumpectomy: superior postoperative pain relief with bupivacaine. J Clin Anesth 1994; 6: 47–51.[Medline]
21 McClure JH. Ropivacaine. Br J Anaesth 1996; 76: 300–7.
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