Plasma concentration of ropivacaine after intercostal blocks for video-assisted thoracic surgery

H. Behnke1, F. Worthmann2, J. Cornelissen2, M. Kahl1 and H. Wulf*,1

1 Department of Anaesthesiology and Intensive Care Medicine, Hospital of the Philipps-University, Baldingerstrasse, D-35033 Marburg, Germany. 2 Department of Anaesthesiology and Intensive Care Medicine, Hospital of the Christian-Albrechts University, Schwanenweg 21, D-24105 Kiel, Germany*Corresponding author

Accepted for publication: February 22, 2002


    Abstract
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Background. Absorption of local anaesthetics following intercostal blocks is rapid. Therefore, plasma concentrations of ropivacaine during intercostal blocks with ropivacaine 2, 5, 7.5 and 10 mg ml–1 (ropivacaine 5 ml injected into each of four intercostal spaces) in patients undergoing video-assisted thoracic surgery were determined.

Methods. After informed consent and ethics committee approval, 64 patients were randomly allocated to four groups for intercostal nerve block (ropivacaine 2, 5, 7.5 or 10 mg ml–1 at the end of surgery). Central (mixed) venous and arterial plasma samples were collected before the start of intercostal application, and 2, 5, 10, 15, 20, 30, 45, 60 and 90 min afterwards. Plasma concentrations of ropivacaine were measured by high performance liquid chromatography.

Results. Maximum venous plasma concentrations occurred after the mean times of 10.7 (range, 5–15), 10.8 (5–20), 11.3 (5–20) and 12.2 (5–45) min, respectively for each group. The groups had mean concentrations of 1.3 (SD, 0.6; range, 0.3–2.3), 2.1 (1.0; 0.5–4.5), 2.4 (1.0; 1.2–5.1) and 2.5 (0.9; 1.7–5.6) µg ml–1, respectively. Maximum arterial plasma concentration following 1.0% ropivacaine occurred after 16 (5–45) min with a mean of 2.3 (0.6; 1.5–3.6) µg ml–1. No signs of central nervous system or cardiac toxicity were observed.

Conclusions. After intercostal blocks the absorption of ropivacaine is rapid compared with other techniques for regional anaesthesia and results in relatively high venous and arterial plasma concentrations, especially if a dose of 100 mg or more is used.

Br J Anaesth 2002; 89: 251–3

Keywords: anaesthetic techniques, regional, intercostal; anaesthetics local, ropivacaine; pharmacokinetics, ropivacaine; toxicity


    Introduction
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Absorption of local anaesthetics following intercostal blocks (ICB) is known to be rapid.1 Ropivacaine is a new long acting amide local anaesthetic available as a pure S-enantiomer.

Several studies have demonstrated that S-ropivacaine is less toxic compared with bupivacaine in preclinical studies25 and is suitable for epidural anaesthesia.69 However, information about the absorption kinetics of ropivacaine following ICB is lacking. In the present study, we measured plasma concentrations of ropivacaine following intraoperative ICB for pain prophylaxis after thoracic surgery using increasing concentrations of ropivacaine (0.2–1.0%).


    Methods
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 Abstract
 Introduction
 Methods
 Results
 Discussion
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Patients (n=64) with ASA classifications of I–III, who were undergoing elective video-assisted thoracoscopic surgery, were enrolled in this prospective study (Table 1). The study protocol had been approved by the ethics committee. After written informed consent had been obtained, patients were premedicated orally with a benzodiazepine. For the induction and maintenance of anaesthesia, propofol, remifentanil and mivacurium were used, and a double lumen tube was inserted for single lung ventilation. A pulmonary artery catheter and an arterial cannula were inserted. After the completion of surgery, but before extubating the trachea, four intercostal blocks were performed as indicated for an appropriate block of the involved nerves. In a prospective randomized manner, 20 ml of the following commercially available solutions of ropivacaine were injected (n=16 in all groups). Group 0.2 received 0.2% ropivacaine (2 mg ml–1), group 0.5, 0.5% ropivacaine (5 mg ml–1), group 0.75, 0.75% ropivacaine (7.5 mg ml–1) and group 1.0, 1.0% ropivacaine (10 mg ml–1).


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Table 1 Patient characteristics and type of video-assisted surgery. Data are presented as mean (range) for age and as mean (SD) for weight and height
 
Intercostal injections were all administered within 2 min. Central mixed venous blood samples from the pulmonary artery catheter were collected before the first intercostal injection and 2, 5, 10, 15, 20, 30, 45, 60 and 90 min after completion of the fourth injection of ropivacaine. In addition, in group 1.0, arterial blood was sampled in order to compare arterial and venous data. Blood samples were centrifuged within 1 h after collection and then stored at –20°C before analysis.

A high performance liquid chromatographic (HPLC) method previously described10 was modified in order to determine plasma concentrations of ropivacaine. All concentrations were determined in duplicate. The absorption was measured at a wavelength of 203 nm and integrated using HPLC-Manager, D-6000 A Interface. The coefficient of variation showed acceptable precision of the assay in the range of 0.01–10 µg ml–1 (<5%).

Data are presented as median, mean, SD and range. For the comparison of maximum plasma concentrations, ANOVA with Dunnett’s post-hoc test was performed using GraphPad Prism, version 3.02 for Windows (GraphPad Software, San Diego, CA, USA). For comparison between arterial and venous plasma concentrations a paired t-test was used. Alpha was set at 0.05. Thus, the study had an 80% chance of detecting an absolute difference of 1 SD within the unpaired comparisons.


    Results
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 Introduction
 Methods
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 Discussion
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Three patients (one in each of the groups 0.2, 0.5 and 0.75) were excluded from further analysis because their sampling processes were incomplete.

On average, maximum central venous plasma concentrations occurred after 11 min, without significant difference between the groups. Mean maximum plasma concentrations were 1.3 (0.6; 0.3–2.3), 2.1 (1.0; 0.5–4.5), 2.4 (1.0; 1.2–5.1) and 2.5 (0.9; 1.7–5.6) µg ml–1 in groups 0.2, 0.5, 0.75 and 1.0, respectively (Fig. 1). The highest individual plasma concentration was 5.6 µg ml–1 5 min after intercostal injection of 1.0% ropivacaine 200 mg. Maximum plasma concentrations were not significantly different between groups 0.5, 0.75 and 1.0 but were significantly higher compared with group 0.2 (P<0.05, P<0.01 and P<0.001, respectively) (Table 2).



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Fig 1 Mean venous plasma concentration of ropivacaine in 61 patients following intercostal blocks (5 ml of either 0.2, 0.5, 0.75 or 1.0% ropivacaine were injected into each of four intercostal spaces). SD is omitted for clarity but see Table 2 for Cmax and Tmax.

 

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Table 2 Maximum plasma concentration of ropivacaine following four intercostal blocks with 5 ml of either 0.2, 0.5, 0.75 or 1.0% ropivacaine. Data for the maximum venous plasma concentration (Cmax), and the time point of that maximum after the start of the injection (Tmax), are given as median (range). For the highest ropivacaine concentration (1.0%), values from venous as well as arterial samples are presented. *P<0.05, **P<0.01 and ***P<0.005 compared with group 0.2
 
Central (mixed) venous plasma concentrations were higher compared with arterial concentrations (group 1.0) 2 min after completion of the blocks (P=0.02), while no significant differences were found in the further time course (e.g. P=0.07 at 5 min) (Fig. 2).



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Fig 2 Time course of the plasma concentration of ropivacaine analysed from central venous and simultaneously drawn arterial blood samples (mean±SD) in 16 patients after intercostal blocks with 1.0% ropivacaine 5 ml injected into each of four intercostal spaces. At 2 min after completion of the blocks, central venous plasma concentrations were significantly higher (P=0.02) compared with arterial plasma concentration.

 
No signs of central nervous system or cardiac toxicity were observed in the patients of the present study.


    Discussion
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Intercostal blocks are associated with rapid absorption of local anaesthetics and, therefore, result in early and relatively high peak plasma concentrations compared with other techniques of regional anaesthesia. The present study shows that this assumption holds true for the new local anaesthetic S-ropivacaine. For example, the mean maximum plasma concentrations after 150 mg epidural ropivacaine were reported to be 1.1–1.4 µg ml–1 after 17–40 min.1114 After an identical dose given for intercostal block (0.75% ropivacaine 20 ml), considerably higher maximum plasma concentrations (2.4 µg ml–1) of ropivacaine were found in the present study with a shorter time to the maximum (11 min).

We found one previous study on the pharmacokinetics of ropivacaine after intercostal blocks in the literature.15 Maximum plasma concentration was 1.1 (0.4) µg ml–1 with 56 ml of 0.25% ropivacaine (140 mg) after 21 min. In our study, peaks occurred somewhat earlier and were considerably higher. This discrepancy could be due to the fact that in the previous study, bilateral blocks (14 blocks each) were performed in awake healthy male volunteers without premedication (n=7; mean age, 34 yr) using 0.25% ropivacaine (a concentration not commercially available). In contrast, we performed four unilateral blocks each in patients of both genders (age range, 44–72 yr) under general anaesthesia.

Toxic plasma ropivacaine concentrations for humans are still not well characterized. Scott and colleagues16 reported mild central nervous symptoms at venous plasma concentrations ranging from 1 to 2 µg ml–1 after i.v. administration of ropivacaine in unpremedicated volunteers. Despite rather high individual plasma concentrations (>5 µg ml–1) no signs of central nervous system or cardiovascular toxicity were observed in our patients, confirming a higher threshold for toxic reactions compared with racemic bupivacaine. A limitation of the present study with regard to toxicity is that our patients were premedicated with a benzodiazepine and general anaesthesia was just finished (blocks were performed before extubating the trachea) at the time of maximum plasma concentrations. Therefore, any signs of central nervous system toxicity could have been suppressed.


    Acknowledgement
 
The authors wish to thank the laboratory assistant Mrs M. Betz for her help with the assays.


    References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
1 Tucker GT, Mather LE. Properties, absorption, and disposition of local anesthetic agents. In: Cousins MJ, Bridenbough PO, eds. Neural Blockade in Clinical Anesthesia and Management of Pain. Philadelphia: Lippincott Company, 1988; 47–111

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4 Moller R, Covino BG. Cardiac electrophysiologic properties of bupivacaine and lidocaine compared with those of ropivacaine, a new amide local anesthetic. Anesthesiology 1990; 72: 322–9[ISI][Medline]

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7 Niesel HC, Eilingsfeld T, Kaiser H, Klimpel L. Ropivacaine for peridural anesthesia. Studies on the dose-response relationship in orthopedic surgery. Reg Anesth 1990; 13: 73–7

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9 Brockway MS, Bannister J, McClure JH, McKeown D, Wildsmith JA. Comparison of extradural ropivacaine and bupivacaine. Br J Anaesth 1991; 66: 31–7[Abstract]

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11 Concepcion M, Arthur GA, Steele SM, Bader AM, Covino BG. A new local anesthetic, ropivacaine. Its epidural effects in humans. Anesth Analg 1990; 70; 80–5[Abstract]

12 Datta S, Camann W, Bader A, Vanderburgh L. Clinical effects and maternal and fetal plasma concentrations of epidural ropivacaine versus bupivacaine for cesarian section. Anesthesiology 1995; 82: 1346–52[ISI][Medline]

13 Katz JA, Knarr D, Bridenbaugh PO. A double blind comparison of 0.5% bupivacaine and 0.75% ropivacaine given epidurally in humans. Reg Anesth 1990; 15: 250–2[ISI][Medline]

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15 Kopacz DJ, Emmanuelsson 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[ISI][Medline]

16 Scott DB, Lee A, Fagan D, Bowler GMR, Bloomfield P, Lundh R. Acute toxicity of ropivacaine compared with that of bupivacaine. Anesth Analg 1989; 69: 562–9





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