1Department of Anaesthesiology and Critical Care Medicine and 2Department of Orthopaedic Surgery, Otto von Guericke University, Magdeburg, Germany*Corresponding author
Accepted for publication: May 5, 2000
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Abstract |
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Br J Anaesth 2000; 85: 8305
Keywords: anaesthetic techniques, analgesia; anaesthetics local, ropivacaine; surgery, orthopaedic; pharmacokinetics
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Introduction |
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The pharmacokinetics of ropivacaine after intravenous infusion,4 8 after infiltration9 and during epidural application10 11 have been demonstrated. Collectively, previous studies concerning continuous epidural analgesia (CEDA),1215 suggest a gradual increase in the plasma concentration of ropivacaine. However, these observations concerned periods of 72 h. The pharmacokinetics of long-term ropivacaine application remain unclear, therefore. As many operations require longer-lasting CEDA,16 17 the principal aim of this study was to evaluate the pharmacokinetics of ropivacaine 2 mg ml1 for CEDA lasting about 120 h, with dose adjustments being made according to clinical need.
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Methods |
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Drug treatment and clinical assessment
Premedication consisted of midazolam and atropine sulfate, injected intramuscularly within 30 min before the patients arrival in the anaesthetic room. Before surgery, an epidural catheter was placed at level L34 or L45 in each patient. The catheter was inserted through an 18-gauge Touhy needle in a cephalic direction 34 cm from the epidural space. After insertion, the catheter was fixed by tunnelling it subcutaneously for 5 cm and suturing it in place. If there was no evidence of intrathecal position after giving a test dose of 30 mg ropivacaine (10 mg ml1), all patients were given a full loading dose of ropivacaine 120150 mg. As a guideline for dosage, 11.2 ml ropivacaine (10 mg ml1) was used per segment. Before surgery, loss of temperature sensation was used to confirm an adequate upper level of sensory blockade. During surgery, midazolam was used to sedate patients. Additional epidural ropivacaine was given if required.
After operation, continuous epidural infusion of ropivacaine (Naropin 2 mg ml1) was started when the motor blockade decreased to 01 on the modified Bromage scale16 or when the sensory blockade dropped below the T8T10 level. We started with an initial infusion rate of ropivacaine 12 mg h1 (2 mg ml1). The infusion rate was adjusted to ensure an adequate clinical level of sensory blockade without motor blockade. The initial infusion rate was increased if the sensory level declined below the level of T12 or if the visual analogue scale (VAS) pain scores increased to >5. Before increasing the infusion rate, a bolus of ropivacaine 4 mg (2 mg ml1) was given.
All patients were connected to a patient-controlled analgesia device (PCA System, Vygon, Aachen, Germany) delivering piritramide. The PCA system was set to deliver piritramide 1 mg per bolus with a lock-out time of 5 min.
Blood sampling and drug assay
Peripheral venous blood samples were taken before the start of epidural injection (time 0) and 1, 2 and 4 h after time 0 on the day of the operation. On the day after surgery, samples were taken at 8 a.m., 12 noon, 4 p.m. and 8 p.m. Samples were also taken on days 25 after surgery at 8 a.m. and 8 p.m., at the end of the infusion and finally 1 and 3 h after infusion was stopped.
All plasma samples were frozen within 1 h of collection and stored at 20°C until assayed. Plasma concentrations were determined at the Justus von Liebig University, Giessen, Germany. The total and free plasma concentrations of ropivacaine base were determined using high pressure liquid chromatography and ultraviolet detection (HPLC/UV), according to the method described by Adams and colleagues,18 with a lower limit of determination of <0.01 µg ml1 and a coefficient of variance of 4%. Recovery rates of 9293% were achieved. Free plasma concentrations were determined after ultrafiltration of the samples using the Amicon micropartition system (MPS-1; Amicon, Beverly, MA, USA). After separation, 600800 µl of plasma protein free ultrafiltrate was extracted. Any pH shift was avoided before ultrafiltration. The 1-acid glycoprotein (AAG) concentrations were measured using a rate nephelometric immunoassay technique (Nephelometer BN 100; Behring, Schwalbach, Germany). The lower limit of quantification was set at 0.01 µg ml1 with an interassay precision of 2.0%.
The patients data were recorded and calculated using Microsoft Excel 7.0. All results are expressed as mean (SD) unless otherwise stated. The graphs were created using Sigmaplot 4.0 (Jandel Scientific, San Rafael, CA, USA).
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Results |
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Pharmacokinetic evaluation
Postoperative epidural ropivacaine infusion was started 5.0 (1.17) h after the first bolus dose of ropivacaine for surgery. The ropivacaine (2 mg ml1) infusion rate was 14.6 (3.2) mg h1 on the day of surgery and was increased to 15.4 ± 4.4 mg h1 on days 15 after surgery. This was equivalent to a ropivacaine dose of 1786 (553) mg. The time course of the infusion rate and the plasma concentrations of ropivacaine is shown in Fig. 1. In two patients (F1 and F9), epidural infusion was stopped after 84 h, at the request of the patients. In five patients (F2, F4, F5, M1 and M2), no dose adjustment was necessary for 100 h. The infusion rate was reduced in three patients (F6, F9 and M3), increased in three patients (F2, F3 and M2), and changed in both directions in two patients (F7 and F8). The duration of infusion and dose adjustments are summarized in Table 1.
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In all patients, the unbound plasma concentration increased steeply during the initial 4 h of epidural ropivacaine infusion. The mean (SD) concentration of unbound ropivacaine was 0.039 (0.02) µg ml1. The individual peak free plasma concentration was 0.096 (0.034) µg ml1. The highest free plasma concentration of ropivacaine (0.16 µg ml1) was noted in patient F9. The free plasma concentration decreased after approximately 70 h in all patients except patient F5, in whom the free concentrationtime profile was stable over the 124 h infusion period. However, in this patient the total plasma concentration of ropivacaine increased throughout the observation period. The decrease in the total and free plasma concentrations of ropivacaine did not correlate with the infusion rate reduction except in patients F6 and F8. In accordance with the low free plasma concentrations, no signs of systemic toxicity were seen in the patients included in this study.
The AAG concentration (Fig. 3) decreased during the first 45 h of epidural infusion. Thereafter, it increased steadily throughout the 120 h follow-up period. The mean concentration of AAG had doubled by the end of infusion (1.55 (0.43) g litre1).
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Discussion |
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In the present study, no evidence of free ropivacaine accumulation in plasma was observed. All free plasma ropivacaine concentrations were below the toxic level reported by Knudsen and colleagues.4 The behaviour of the free ropivacaine concentration corresponds with previous observations.1215 Notably, we confirm the observation of Scott and colleagues15 that the mean free ropivacaine concentration plateaus and decreases after approximately 70 h. This time course of the unbound drug could be due to variation in plasma protein binding.20
As shown in Fig. 2, after a minor decline immediately after surgery, the AAG concentration steadily increased. The initial dip in AAG concentration could have been caused by fluid replacement during the operation. This phenomenon has been reported after different types of surgery;15 21 in both of these studies, initial reductions in plasma AAG concentration were associated with decreased plasma drug binding and therefore increased free fractions. The subsequent increase in plasma AAG concentration is probably related to surgical stress.17 22 Our data suggest that the increase in AAG concentration after surgery is not inhibited by epidural analgesia. This is in accordance with results reported by Wulf and colleagues;23 one possible explanation for this finding is that complete suppression of the stress response requires complete sympathetic and somatic blockade of the surgical site such as can be provided only with extensive epidural anaesthesia.17
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The time course of the total ropivacaine concentration beyond 72 h has not yet been reported. Unexpectedly, we found that the total ropivacaine concentration began to decrease after approximately 68 h, and continued to decrease until the end of infusion. Thus would contradict the previous assumption that ropivacaine would probably accumulate in the plasma.1215 A steady state total plasma concentration was not found, probably because it did not yet equilibrated. The decrease in the total plasma concentration may be have involved the major pathway of ropivacaine metabolism, by the P450 cytochromes CYP1A2 and CYP3A4.27 28 Since chronic application of drugs that are metabolized by cytochrome P450, e.g. cocaine,29 theophylline and midazolam,30 can induce metabolism of cytochrome P450, it is possible that a similar phenomenon could be responsible for the decrease in the total and free plasma concentration of ropivacaine during chronic administration. Any other incidents interfering with ropivacaine metabolism can be excluded in our study.
We have shown that, during chronic administration of ropivacaine, the free plasma concentrations were well below the toxic concentration, emphasizing the safety and efficacy of long-term ropivacaine CEDA. The deductions that can be made from the results of our study are limited by the small number of patients. Further studies of long-term ropivacaine administration are needed.
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Acknowledgements |
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References |
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