High plasma ropivacaine concentrations after fascia iliaca compartment block in children

O. Paut*,1, E. Schreiber2, F. Lacroix1, V. Meyrieux1, N. Simon2, T. Lavrut2, J. Camboulives1 and B. Bruguerolle2

1 Department of Paediatric Anaesthesia, Children CHU Timone Hospital, 13385 Marseille Cedex 5, France. 2 Medical and Clinical Pharmacology Department, CHU Timone, 13385 Marseille Cedex 5 France

*Corresponding author. E-mail: olivier.paut@mail.ap-hm.fr

Accepted for publication: September 9, 2003


    Abstract
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 Abstract
 Introduction
 Methods and results
 Comment
 References
 
Background. The pharmacokinetic profile of local anaesthetics is influenced by the mode of administration. We sought to compare the pharmacokinetics of two doses of ropivacaine after fascia iliaca compartment (FIC) block in children.

Methods. In this prospective, double-blind study, children received an FIC block as a part of their anaesthetic management during elective orthopaedic surgery on the thigh. They were randomized to receive ropivacaine 0.7 ml kg–1 using either a 0.375% or 0.5% solution. Venous blood samples were drawn up to 6 h after injection. Plasma concentrations of ropivacaine were measured by gas–liquid chromatography.

Results. Six children (10.2 (range 5–15) yr, 35.6 (SD 10) kg were included. FIC block provided satisfactory peroperative pain relief. No signs of toxicity were observed, but high maximal plasma concentrations (Cmax 4.33–5.6 µg ml–1), were observed for three of four patients in the ropivacaine 0.5% group. The two patients in the 0.375% group showed values within the safe range (Cmax 0.66 and 0.98 µg ml–1 respectively). Even though no toxic effects were observed, these results led us to discontinue the study.

Conclusions. The administration of ropivacaine 3.5 mg kg–1 can be associated with sustained high plasma concentrations of ropivacaine, outside the tolerable range. In view of these results, we recommend the use of lower ropivacaine dosage during FIC block in children.

Br J Anaesth 2004: 92: 416–18

Keywords: anaesthesia, paediatrics; anaesthetic techniques, fascia iliaca compartment block; anaesthetics local, ropivacaine; pharmacokinetics; pharmacology


    Introduction
 Top
 Abstract
 Introduction
 Methods and results
 Comment
 References
 
Ropivacaine is a new long-acting local anaesthetic drug which produces central nervous system symptoms at higher doses, and less cardiovascular changes than bupivacaine.1 Pharmacokinetic properties of this drug have been described in caudal anaesthesia in children2 and in ilioinguinal nerve block3 but the pharmacokinetics of ropivacaine have not been characterized in fascia iliaca compartment (FIC) block.

The aim of this study was to compare the pharmacokinetic characteristics of two doses of ropivacaine in FIC block in children undergoing orthopaedic surgery.


    Methods and results
 Top
 Abstract
 Introduction
 Methods and results
 Comment
 References
 
This prospective, double-blind, randomized study was approved by the local ethics committee and written consent was obtained from the parents and children. Six ASA I or II children (10.2 (range 5–15) yr, 35.6 (SD 10) kg undergoing elective orthopaedic surgery on the thigh were included. Premedication consisted of either oral hydroxyzine 1.5 mg kg–1 or rectal midazolam 0.4 mg kg–1. Anaesthesia was induced with either sevoflurane or propofol 3–5 mg kg–1 and alfentanil 10 µg kg–1. A laryngeal mask airway was inserted and the lungs were mechanically ventilated. Anaesthesia was maintained with sevoflurane (1 MAC, adapted to age) and nitrous oxide in oxygen (70%/30%). Alfentanil 10 µg kg–1 was administered if the patient showed signs of pain during surgery, defined as a 20% minimum increase from baseline in heart rate or blood pressure.

The FIC block was performed at least 15 min before surgery in anaesthetized patients. FIC block was performed using the technique of Dalens and colleagues.4 The puncture point was 0.5–1 cm below the inguinal ligament, at the union of the lateral one-third and medial two-thirds of the line between the pubic tubercle and anterior superior iliac spine. The needle was introduced at a 45–60° angle with the skin, until the perception of two losses of resistance corresponding to the crossing of the fascia lata and then the fascia iliaca. The children were randomly assigned to receive either ropivacaine 0.7 ml kg–1, 0.5% (0.5% group) or 0.375% (0.375% group). Venous blood samples (1 ml) were collected from a peripheral venous catheter dedicated to blood sampling, before and 5, 10, 20, 30, 45, 60, 90, 120, 240 and 360 min after completion of the block. After centrifugation, plasma samples were stored at –20°C. Total plasma concentrations of ropivacaine were measured by gas–liquid chromatography using nitrogen/phosphorus detection according to a method previously reported for bupivacaine analysis,5 and modified for ropivacaine determination. The limit of quantification was 15 ng ml–1. The area under the ropivacaine concentration curve (AUC) was determined by the trapezoidal rule.

At the end of the procedure, the anaesthetist evaluated the quality of analgesia provided by the FIC block during surgery using a four-point scale (excellent, good, moderate, poor). Postoperative pain at rest and on mobilization was assessed using a visual analogue scale (children >6 yr) or the Objective Pain Scale (children <6 yr), at each sampling time and then every 4 h during the first postoperative day. In case of insufficient analgesia, i.v. morphine 50 µg kg–1 and/or i.v. propacetamol 30 mg kg–1 was administered. Every side-effect was recorded in the protocol chart.

Four patients were included in the 0.5% group and two in the 0.375% group. Median duration of surgery was 92 min. The time course of plasma ropivacaine concentrations is reported in Figure 1 and the individual pharmacokinetic values are listed in Table 1. In the 0.5% group, high Cmax (4.33–5.6 µg ml–1) was observed for three patients, and one patient had ropivacaine plasma concentrations within the expected range (Cmax=1.85 µg ml–1). In the 0.375% group, both patients showed Cmax values within the safety range (1.05 and 0.86 µg ml–1, respectively). These Cmax concentrations were reached after a time (tmax) ranging between 20 and 90 min.



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Fig 1 Time course of ropivacaine plasma concentrations in six children receiving 0.7 ml kg–1 of a 0.5% solution (3.5 mg kg–1, filled circles) or 0.7 ml kg–1 of a 0.375% solution (2.6 mg kg–1, open circles). The horizontal line represents the maximal plasma concentration accepted in literature.

 

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Table 1 Patient and pharmacokinetic characteristics
 
One patient needed a single alfentanil bolus at the beginning of surgery. Peroperative analgesia provided by FIC block was considered excellent for all patients. Ropivacaine was well tolerated. None of the patients reported symptoms of toxicity and no ECG abnormalities were observed during ropivacaine injection and anaesthesia. Satisfactory postoperative pain relief was obtained in all patients. Four children needed a single dose of morphine during the 24-h study duration.


    Comment
 Top
 Abstract
 Introduction
 Methods and results
 Comment
 References
 
This study showed that high values of venous plasma ropivacaine can be observed in children receiving ropivacaine 3.5 mg kg–1 administered via an FIC block. In three patients among the four who received this dosage Cmax was well above the mean maximum tolerated plasma concentration (2.2 µg ml–1).1 These high plasma concentrations were not associated with any observable toxicity in the patients. However, signs and symptoms of neurotoxicity could have been masked by general anaesthesia, as tmax occurred during anaesthesia or the early stage of recovery. Therefore, this study, which was designed to involve a total of 20 patients, was discontinued.

The pharmacokinetics of ropivacaine administered for a peripheral block has been studied in two recent paediatric series.3 6 After using ropivacaine 3 mg kg–1 for an ilioinguinal nerve block, providing effective post-operative analgesia, Dalens and colleagues reported a mean Cmax of 1.5 µg ml–1 and tmax between 15 and 64 min.3 Two children developed a high ropivacaine Cmax (3.1 and 4.8 µg ml–1). The corresponding fu was 3.5 and 0.6% respectively, providing plasma concentrations of free ropivacaine below the threshold concentrations for toxicity (0.15 (0.08) µg ml–1). In another study, ropivacaine 0.75% 2 mg kg–1 was administered in children during ilioinguinal–iliohypogastric nerve block.6 Mean Cmax was 1.5 µg ml–1 and tmax was 35 min.6

How can we explain such high ropivacaine plasma concentrations in our patients? Intravenous absorption of local anaesthetics is one complication that may be encountered during regional anaesthesia.7 This has not been previously described during FIC block and seems unlikely in our patients as the injection point is distant from a vessel.4 Furthermore, the occurrence of blood reflux within the needle and tube was checked frequently during injection. Obviously, in the case of i.v. administration, the Cmax should have been reached early, yielding a tmax shorter than those in our study (between 20 and 45 min). A second possible cause for these high plasma concentrations is that it is possible to administer a local anaesthetic intramuscularly while performing an FIC block. The close relationship between the lumbar plexus and the psoas major can explain this possibility.8 A third explanation could be an inappropriate ropivacaine dosage. In this study, we used a maximal dose of ropivacaine 3.5 mg kg–1 to achieve an FIC block. This dose is close to that used by Dalens and colleagues during ilioinguinal block3 and by others during caudal block in children.9 Due to the presence of many richly vascularized muscles within the fascia iliaca compartment, rapid absorption during an FIC block may occur, leading to high ropivacaine plasma concentrations.4 We speculate that the ropivacaine 3.5 mg kg–1 dose used in three children, combined with the rapid resorption of local anaesthetics during FIC block, could explain the high ropivacaine concentrations. In this case, the use of lower doses of ropivacaine during an FIC block should be safer. This is supported by the acceptable Cmax we found in the two children receiving ropivacaine 2.6 mg kg–1. However, the safety of ropivacaine 0.7 ml kg–1 0.375% has to be demonstrated, since only two patients were included in this study group.


    Acknowledgement
 
The authors thank Patrice Aubin, MD, for his help in reviewing the manuscript.


    References
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 Abstract
 Introduction
 Methods and results
 Comment
 References
 
1 Knudsen K, Beckman Suurkula M, Blomberg S, Sjovall 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]

2 Lonnqvist P, Westrin P, Larsson B, et al. Ropivacaine pharmacokinetics after caudal block in 1–8 year old children. Br J Anaesth 2000; 85: 506–11[Abstract/Free Full Text]

3 Dalens B, Ecoffey C, Joly A, et al. Pharmacokinetics and analgesic effect of ropivacaine following ilioinguinal/iliohypogastric nerve block in children. Paediatr Anaesth 2001; 11: 415–20[CrossRef][ISI][Medline]

4 Dalens B, Vanneuville G, Tanguy A. Comparison of the fascia iliaca compartment block with the 3-in-1 block in children. Anesth Analg 1989; 69: 705–13[Abstract]

5 Lorec A, Bruguerolle B, Attolini L, Roucoules X. Rapid simultaneous determination of lidocaine, bupivacaine and their two main metabolites using capillary gas liquid chromatography with nitrogen phosphorus detector. Ther Drug Monit 1994; 16: 592–5[ISI][Medline]

6 Ala-Kokko TI, Karinen J, Räihä E, Kiviluoma K, Alahuhta S. Pharmacokinetics of 0.75% ropivacaine and 0.5% bupivacaine after ilioinguinal-iliohypogastric nerve block in children. Br J Anaesth 2002; 89: 438–41[Abstract/Free Full Text]

7 Thong W, Pajel V, Khalil S. Inadvertent administration of intravenous ropivacaine in a child. Paediatr Anaesth 2000; 10: 563–4[CrossRef][ISI][Medline]

8 Farny J, Drolet P, Girard M. Anatomy of the posterior approach to the lumbar plexus block. Can J Anaesth 1994; 41: 480–5[Abstract]

9 Da Conceicao MJ, Coelho L. Caudal anaesthesia with 0.375% ropivacaine or 0.375% bupivacaine in paediatric patients. Br J Anaesth 1998; 80: 507–8[CrossRef][ISI][Medline]