Ropivacaine plasma concentrations during 120-hour epidural infusion

D. Wiedemann1, B. Mühlnickel1, E. Staroske1, W. Neumann2 and W. Röse *,1

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


    Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
The pharmacokinetics of ropivacaine were evaluated during long-term continuous epidural analgesia (CEDA) for about 120 h. The total and free plasma concentrations of ropivacaine and the {alpha}1-acid glycoprotein (AAG) concentration were measured in 12 patients after total knee arthroplasty. The infusion rate was adjusted according to patients’ analgesic needs or side effects. The mean (SD) rate of infusion of ropivacaine (Naropin 2 mg ml–1) was 14.6 (3.2) mg h–1 on the day of surgery and was increased after surgery to 15.4 (4.4) mg h–1 on days 1–5. This was equivalent to an absolute dose of 1786 (553) mg of ropivacaine over the entire infusion period. After an initial increase, the mean free ropivacaine plasma concentration nearly plateaued and than decreased slightly after approximately 70 h. The individual peak free plasma concentration was 0.096 (0.034) µg ml–1. The highest individual free plasma concentration was 0.16 µg ml–1. The individual peak total plasma concentration, 4.1 (1.2) µg ml–1, was achieved after 67.7 (16.5) h, although the AAG concentration increased throughout the observation period. Our data support the safety and efficacy of long-term ropivacaine CEDA.

Br J Anaesth 2000; 85: 830–5

Keywords: anaesthetic techniques, analgesia; anaesthetics local, ropivacaine; surgery, orthopaedic; pharmacokinetics


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Ropivacaine (Naropin) is a long-acting amide local anaesthetic, structurally closely related to bupivacaine. It appears to produce less blockade of motor fibres than bupivacaine but with similar sensory blockade.1 2 Earlier studies3 4 suggest an increased safety margin before onset of toxic side effects after treatment with ropivacaine, compared with other local anaesthetics. Other studies have shown that ropivacaine is suitable for postoperative epidural analgesia.5–7

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 ml–1 for CEDA lasting about 120 h, with dose adjustments being made according to clinical need.


    Methods
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Patients
After obtaining approval from the Ethics Committee of the Otto von Guericke University, Magdeburg, and written informed consent, we studied 15 patients after total knee arthroplasty. Patients were considered eligible for the study if they were aged 18–85 yr, weighed 50–120 kg and were of ASA status I–III. None of the patients had intrinsic abnormalities of hepatic or renal function, or had neurological or mental diseases or any conditions that would interfere with the ability to assess pain after surgery. Only patients who received one particular type of joint replacement (Natural Knee endoprosthesis; Sulzer Medica, Switzerland) were included.

Drug treatment and clinical assessment
Premedication consisted of midazolam and atropine sulfate, injected intramuscularly within 30 min before the patient’s arrival in the anaesthetic room. Before surgery, an epidural catheter was placed at level L3–4 or L4–5 in each patient. The catheter was inserted through an 18-gauge Touhy needle in a cephalic direction 3–4 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 ml–1), all patients were given a full loading dose of ropivacaine 120–150 mg. As a guideline for dosage, 1–1.2 ml ropivacaine (10 mg ml–1) 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 ml–1) was started when the motor blockade decreased to 0–1 on the modified Bromage scale16 or when the sensory blockade dropped below the T8–T10 level. We started with an initial infusion rate of ropivacaine 12 mg h–1 (2 mg ml–1). 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 ml–1) 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 2–5 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 ml–1 and a coefficient of variance of 4%. Recovery rates of 92–93% 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, 600–800 µl of plasma protein free ultrafiltrate was extracted. Any pH shift was avoided before ultrafiltration. The {alpha}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 ml–1 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).


    Results
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Epidural anaesthesia was satisfactory in all patients. After the start of surgery, one patient required an additional dose of 30 mg ropivacaine (10 mg ml–1). For three patients, CEDA was stopped prematurely for the following technical reasons: epidural catheter displacement; interruption of infusion for 3 h; and misfilling of the injection pump. Therefore, plasma concentrations of ropivacaine and the AAG concentration were measured in 12 patients. The mean (SD) patient age was 68.8 (7.28) yr, height 164 (7) cm and weight 85 (16) kg. The dose of ropivacaine (10 mg ml–1) used for epidural anaesthesia was 156 (18) mg. A sensory level of T6±1 was achieved. The duration of surgery was 72.9 (19.6) min.

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 ml–1) infusion rate was 14.6 (3.2) mg h–1 on the day of surgery and was increased to 15.4 ± 4.4 mg h–1 on days 1–5 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.



View larger version (50K):
[in this window]
[in a new window]
 
Fig 1 Individual time course of the total and free plasma concentration and the epidural infusion rate of ropivacaine using Naropin 2 mg ml–1.

 

View this table:
[in this window]
[in a new window]
 
Table 1 Details of the postoperative epidural infusion of ropivacaine (Naropin 2 mg ml–1). aTimes at which infusion rate was changed are given in hours after the beginning of infusion. F = female, M = male
 
In most of our patients (F1–8 and M1–2), the total ropivacaine concentration increased after surgery until day 3. The individual peak total plasma concentrations (Cmax) of all patients ranged between 2.39 and 6.08 µg ml–1, with a mean (SD) of 4.1 (1.2) µg ml–1. The average Cmax was achieved at 67.7 (16.5) h. However, in two patients (F9 and M3), Cmax was achieved after only a few hours of epidural infusion. Initially, a higher infusion rate was required for both patients because of high pain levels. Therefore the free and total plasma concentrations of ropivacaine were much higher than those in all other patients on the day of surgery. The necessary adjustments in infusion rates resulted in a decrease in ropivacaine plasma concentrations in both patients. The increase in ropivacaine concentrations until day 3 after surgery could have been concealed by these dose reductions.

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 ml–1. The individual peak free plasma concentration was 0.096 (0.034) µg ml–1. The highest free plasma concentration of ropivacaine (0.16 µg ml–1) was noted in patient F9. The free plasma concentration decreased after approximately 70 h in all patients except patient F5, in whom the free concentration–time 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 4–5 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 litre–1).



View larger version (15K):
[in this window]
[in a new window]
 
Fig 3 Variation of the mean(SD) plasma concentration of {alpha}1,-acid glycoprotein (AAG) with time.

 

    Discussion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
This study was performed to evaluate the pharmacokinetics of ropivacaine during 120 h of CEDA. It is well known that the toxic effects of local anaesthetics are more closely related to the free plasma concentration than to the total concentration, as only free drug can reach receptor sites.19 As reported by Knudsen and colleagues,4 the CNS toxicity threshold of free ropivacaine concentration is estimated to be between 0.34 and 0.85 µg ml–1. However, this value is valid only for intravenous administration of ropivacaine. As explained by Santos and colleagues,3 slower administration of ropivacaine will allow more extensive redistribution of the drug so that toxic manifestations may occur at higher doses but lower blood concentrations of drug.

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



View larger version (52K):
[in this window]
[in a new window]
 
Fig 2 Individual time course of the total and free plasma concentration and the epidural infusion rate of ropivacaine using Naropin 2 mg ml-1.

 
The increase in total ropivacaine concentration up to 72 h has been observed before15 and is thought to be caused by increased protein binding.24 25 According to Burm,26 the increasing total plasma concentration during the first 3 days reflects changes in plasma protein binding, related to increased AAG concentrations after surgery, so that increased total plasma concentrations are not accompanied by similar increases in the more important free drug concentration. These changes in plasma drug binding may have importance for the interpretation of total plasma drug concentrations. We found that the AAG concentration increased until the end of our observation period, in accordance with Wulf,23 who reported that AAG concentration was maximal between 6 and 12 days after hip surgery.

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.


    Acknowledgements
 
Particular thanks are given to Mr H. Bauer (Astra GmbH, Germany) for helpful discussions. We also thank Prof. Dr C.-W. Wallesch, Department of Neurology, Otto von Guericke University, Magdeburg, for laboratory space. Dr U. J. Erkens and Mrs B. Weber (Department of Anaesthesiology and Intensive Care Medicine, Justus von Liebig University, Giessen) and Dr S. Kropf (Institute of Biometrics and Medical Informatics, Otto von Guericke University, Magdeburg), are thanked for their contributions.This work was supported by Astra GmbH, Germany.


    References
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
1 Bader AM, Datta S, Flanagan H, Covino BG. Comparison of bupivacaine- and ropivacaine-induced conduction blockade in the isolated rabbit vagus nerve. Anesth Analg 1989; 68: 724–7[Abstract]

2 Morrison LMM, Emanuelsson BM, McClure JH et al. Efficacy and kinetics of extradural ropivacaine: comparison with bupivacaine. Br J Anaesth 1994; 72: 164–9[Abstract]

3 Santos AC, Arthur GR, Wlody D, De Armas P, Morishima HO, Finster M. Comparative systemic toxicity of ropivacaine and bupivacaine in nonpregnant and pregnant ewes. Anesthesiology 1995; 82: 734–40[ISI][Medline]

4 Knudsen K, Beckman Suurküla M, Blomberg S, Sjövall J, Edvardsson N. Central nervous and cardiovascular effects of i.v. infusions of ropivacaine, bupivacaine and placebo in volunteers. Br J Anaesth 1997; 78: 507–14[Abstract/Free Full Text]

5 Wulf H, Biscoping J, Beland B, Bachmann-Mennenga B, Motsch J. Ropivacaine epidural anesthesia and analgesia versus general anesthesia and intravenous patient-controlled analgesia with morphine in the perioperative management of hip replacement. Anesth Analg 1999; 89: 111–16[Abstract/Free Full Text]

6 Jayr C, Beaussier M, Gustafsson U et al. Continuous epidural infusion of ropivacaine for postoperative analgesia after major abdominal surgery: comparative study with i.v. PCA morphine. Br J Anaesth 1998; 81: 887–92[Abstract/Free Full Text]

7 Thomas JM, Schug SA. Recent advances in the pharmacokinetics of local anaesthetics. Long-acting amide enantiomers and continuous infusions. Clin Pharmacokinet 1999; 36: 67–83[ISI][Medline]

8 Lee A, Fagan D, Lamont M, Tucker GT, Halldin M, Scott DB. Disposition kinetics of ropivacaine in humans. Anesth Analg 1989; 69: 736–8[Abstract]

9 Petterson N, Emanuelsson BM, Reventlid H, Hahn RG. High-dose ropivacaine wound infiltration for pain relief after inguinal hernia repair. A clinical and pharmacokinetic evaluation. Reg Anesth Pain Med 1998; 23: 189–96[ISI][Medline]

10 McCrae AF, Westerling P, McClure JH. Pharmacokinetic and clinical study of ropivacaine and bupivacaine in women receiving extradural analgesia in labour. Br J Anaesth 1997; 79: 558–62[Abstract/Free Full Text]

11 Emanuelsson BK, Persson J, Alm C, Heller A, Gustafsson LL. Systemic absorption and block after epidural injection of ropivacaine in healthy volunteers. Anesthesiology 1997; 87: 1309–17[ISI][Medline]

12 Emanuelsson BM, Zaric D, Nydal PA, Axelsson KH. Pharmacokinetics of ropivacaine and bupivacaine during 21 hours of continuous epidural infusion in healthy male volunteers. Anesth Analg 1995; 81: 1163–8[Abstract]

13 Erichsen CJ, Sjövall J, Kehlett H, Hedlund C, Arvidsson T. Pharmacokinetics and analgesic effect of ropivacaine during continuous epidural infusion for postoperative pain relief. Anesthesiology 1996; 84: 834–42[ISI][Medline]

14 Irestedt L, Ekblom A, Olofsson C, Dahlström AC, Emanuelsson BM. Pharmacokinetics and clinical effect during continuous epidural infusion with ropivacaine 2.5 mg/ml or bupivacaine 2.5 mg/ml for labour pain relief. Acta Anaesthesiol Scand 1998; 42: 890–6[ISI][Medline]

15 Scott DA, Emanuelsson BM, Mooney PH, Cook RJ, Junestrand C. Pharmacokinetics and efficacy of long-term epidural ropivacaine infusion for postoperative analgesia. Anesth Analg 1997; 85: 1322–30[Abstract]

16 Markham A, Faulds D. Ropivacaine: a review of its pharmacology and therapeutic use in regional anaesthesia. Drugs 1996; 52: 429–49[ISI][Medline]

17 Liu S, Carpenter RL, Neal JM. Epidural anesthesia and analgesia: their role in postoperative outcome. Anesthesiology 1995; 82: 1474–506[ISI][Medline]

18 Adams HA, Biscoping J, Ludolf K, Borgmann A, Bachmann-M B, Hempelmann G. Die quantitative Analyse von Amid-Lokalanaesthetika mittels Hochdruck-Flüssigkeits-Chromatographie und UV-Detektion (HPLC/UV). Reg Anaesth 1989; 12: 53–7[Medline]

19 Alahuta S, Ala-Kokko TI. Ropivacaine: a new agent for epidural labour analgesia? Acta Anaesthesiol Scand 1998; 42: 887–9[ISI][Medline]

20 Rutten AJ, Mather LE, Plummer JL, Henning EC. Postoperative course of plasma protein binding of lignocaine, ropivacaine and bupivacaine in sheep. J Pharm Pharmacol 1992; 44: 355–8[ISI][Medline]

21 Davies RF, Dube LM, Mousseau N, McGilveray I, Beanlands DS. Perioperative variability of binding of lidocaine, quinidine, and propranolol after cardiac operations. J Thorac Cardiovasc Surg 1988; 96: 634–41

22 Jeejeebhoy KN, Ho J, Mehra R, Jeejeebhoy J, Bruce-Robertson A. Effects of hormones on the synthesis of {alpha}1 (acute-phase) glycoprotein in isolates rat hepatocytes. Biochem J 1977; 168: 347–52

23 Wulf H, Winckler K, Maier C, Heinzow B. Pharmacokinetics and protein binding of bupivacaine in postoperative epidural analgesia. Acta Anaesthesiol Scand 1988; 32: 530–4

24 Routledge PA. The plasma protein binding of basic drugs. Br J Clin Pharmacol 1986; 22: 499–506[ISI][Medline]

25 Tucker GT. Pharmacokinetics of local anaesthetics. Br J Anaesth 1986; 58: 717–31[ISI][Medline]

26 Burm AGL. Clinical pharmacokinetics of epidural and spinal anaesthesia. Clin Pharmacokinet 1989; 16: 283–311[ISI][Medline]

27 Arlander E, Ekström G, Alm C et al. Metabolism of ropivacaine in humans is mediated by CYP1A2 and to a minor extent by CYP3A4: an interaction study with fluvoxamine and ketoconazole as in vivo inhibitors. Clin Pharmacol Ther 1998; 64: 484–91

28 Oda Y, Furuichi K, Tanaka K et al. Metabolism of a new local anesthetic, ropivacaine, by human hepatic cytochrome P450. Anesthesiology 1995; 82: 214–20

29 Powers JF, Shuster L. Subacute cocaine treatment changes expression of mouse liver cytochrome P450 isoforms. Pharmacology 1999; 58: 87–100

30 Pelkonen O, Maenpaa J, Taavitsainen P, Rautio A, Raunio H. Inhibition and induction of human cytochrome P450 (CYP) enzymes. Xenobiotica 1998; 28: 1203–53