Pharmacokinetics and clinical efficacy of long-term epidural ropivacaine infusion in children{dagger}

T. G. Hansen1,*, K. F. Ilett2, S. I. Lim1, C. Reid1, L. P. Hackett3 and R. Bergesio1

1Department of Paediatric Anaesthesia, Princess Margaret Hospital for Children, Subiaco, 6001 Western Australia, Australia. 2Department of Pharmacology, University of Western Australia, Nedlands, 6907 Western Australia, Australia. 3Clinical Pharmacology & Toxicology Laboratory, The Western Australian Centre for Pathology & Medical Research, Nedlands, 6009 Western Australia, Australia

{dagger}This article is acompanied by Editorial II.

Accepted for publication: December 12, 1999


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The clinical efficacy and pharmacokinetics of long-term epidural ropivacaine infusion were investigated in 18 postoperative children aged between 0.3 and 7.3 yr. A lumbar or thoracic epidural catheter was inserted after the anaesthetic induction. Sixty minutes following a bolus dose of ropivacaine 1 mg kg–1, 0.2% ropivacaine was infused at a fixed rate of 0.4 mg kg–1 h–1 for a mean of 61.3 h (range 36–96 h). Clinical evaluation comprised hourly recording of pain, sedation, motor block, nausea/vomiting, pruritus-scores, SpO2, pulse and respiratory rates, and recording of non-invasive arterial pressure every 4 h. Total and free plasma concentrations were measured by high-performance liquid chromatography at 0, 1, 6, 12, 24, 36, 48, 72 and 96 h. Analgesia was of high quality and side effects were minor. No clinical signs of local anaesthetic toxicity were seen. Total (100–3189 µg litre–1) and free (10–56 µg litre–1) ropivacaine concentrations were within the range reported to be ‘safe’ in previous studies in adults. Mean (95% CI) volume of distribution was 3.1 litre kg–1 (2.1–4.2 litre kg–1), total clearance was 8.5 ml kg–1 min–1 (5.8–11.1 ml kg–1 min–1), free clearance was 220 ml kg–1 min–1 (170–270 ml kg–1 min–1) and elimination half-life was 4.9 h (3.0–6.7 h).

Br J Anaesth 2000; 85: 347–53

Keywords: anaesthetics, local; anaesthetic techniques, epidural; paediatric pharmacokinetics


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Ropivacaine, a new long-acting aminoamide local anaesthetic, has been shown to have a lower potential to produce central nervous system and cardiovascular toxicity and to reduce motor block in adults compared with bupivacaine.14 Hence, ropivacaine may be the ideal local anaesthetic for epidural infusion in paediatric patients.

To date, ropivacaine has not been approved for the use in children under the age of 12 yr and only a few paediatric studies of epidural (i.e. caudal bolus doses) ropivacaine have been reported.511 The concept of epidural ropivacaine infusion in children has been addressed in a letter,12 but no data are available describing the pharmacokinetics of continuous long-term epidural ropivacaine infusion in children.

The aims of this study were to determine the clinical efficacy, plasma ropivacaine (total and free) concentrations and pharmacokinetics of long-term continuous epidural infusion in children following major surgery. An open design was chosen because continuous epidural use of the drug in children had not been studied previously.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patients and drug administration
After approval by the Princess Margaret Hospital Ethics Committee and written informed parental consent, 18 children (ASA I–II, age >3 months, <8 yr) undergoing major elective abdominal, urologic or orthopaedic surgery were included in this study. Apart from EMLA, no premedication was given to any of the children. General anaesthesia was induced with either 8% sevoflurane in oxygen or i.v. propofol 3–5 mg kg–1, and endotracheal intubation was facilitated by vecuronium (0.1 mg kg–1). Anaesthesia was maintained with oxygen (35%), nitrous oxide (65%), isoflurane (0.5–1.0%) and i.v. fentanyl (2–5 µg kg–1).

A 0.9-mm (~20-gauge) epidural catheter was inserted via the lumbar or low thoracic route under sterile conditions using a 18-gauge Tuohy needle (Portex Minipack System, Hythe, Kent, UK) and a ‘loss-of-resistance’ technique with normal saline. The level of the insertion depended on the type of surgery. Correct placement of the catheter was confirmed by negative aspiration of blood and cerebrospinal fluid. No test dose was used.

Before surgery, a bolus dose of 0.5 ml (1 mg) kg–1 0.2% ropivacaine (Naropin, Astra Pharmaceuticals, NSW, Australia) was given over a period of 10 min. Sixty minutes later, a continuous infusion of 0.2% ropivacaine was commenced at a rate of 0.4 mg kg–1 h–1. No extra bolus doses were allowed. Paracetamol 15–20 mg kg–1 p.o. or p.r. was given every 6 h as additional analgesia. If pain scores were >3/10, rescue analgesia with i.v. bolus doses of morphine 25 µg kg–1 was given. Intraoperative fluid management comprised Ringer’s lactate at a rate of 5–10 ml kg–1 h–1.

Postoperatively, all children were monitored according to a protocol comprising hourly recording of pulse and respiratory rates, SpO2, observational pain score (numerical 0–10), sedation score (X=normal sleep, 0=awake and alert, 1=drowsy, rousable to verbal commands, 2=drowsy, rousable to shaking, 3=unrousable), motor block score (0=no movement, 1=ankle only, 2=ankle and knee, 3=ankle, knee and hip), postoperative nausea and vomiting score (0=nil, 1=resolved without treatment, 2=respond to treatment, 3=no response to treatment), and pruritus score (0=nil, 1=mild, respond to topical treatment, 2=moderate, respond to systemic treatment, 3=severe, despite systemic treatment). Arterial pressure was measured non-invasively at every 4 h.

All children had an urinary catheter inserted intraoperatively. Specific problems such as drug errors, equipment malfunction and epidural catheter-related problems (disconnection, leakage, local inflammation and pressure areas) were recorded.

Blood sampling
Venous blood samples (1.5–2 ml) were taken from a peripheral i.v. catheter (20- or 22-gauge, InsyteTM, Becton Dickinson Infusion Therapy Systems, Sandy, UT, USA). A baseline sample was taken after induction, and further samples were taken at 1, 6, 12, 24, 36 and 48 h after the start of the infusion, or for as long as sampling from the cannula was possible. If the ropivacaine infusion continued beyond 48 h, additional samples were taken every 24 h. After each blood sampling, the i.v. catheter was flushed with heparinized saline (1–2 ml). Blood samples were separated by centrifugation at 1500 g for 5 min and plasma stored at –20°C prior to assay.

Measurement of total ropivacaine concentration
Following the addition of bupivacaine (300 ng) as an internal standard, 0.5 ml plasma was adjusted to pH 9.2 by the addition of 0.5 ml 2% sodium tetraborate, and the analytes were extracted into 10 ml diethylether by shaking vigorously for 5 min. After centrifugation (2000 g for 5 min), the organic phase was back-extracted into 0.2 ml 0.1 M H2SO4 by shaking well for 1 min. After discarding the organic phase, aliquots of the acid were injected onto the HPLC. The HPLC system consisted of a Merck LiChrospher RP Select B column (250x4 mm) and a solvent of 25% acetonitrile in 45 mM phosphate buffer pH 3. Eluting compounds were detected by their absorbance at 220 nm. Plasma ropivacaine concentrations were interpolated from a plot of peak height ratio (ropivacaine : bupivacaine) versus ropivacaine added to blank plasma (0–1200 µg litre–1). The correlation coefficient over the concentration range 100–800 µg litre–1 was 0.9999. The coefficient of variation over the concentration range 150–700 µg litre–1 was between 1.5 and 2.5%, and the limit of quantification was 10 µg litre–1. Samples above the highest concentration of the standard curve were re-assayed using smaller aliquots to ensure that the assays fell within the stated range.

Measurement of free plasma ropivacaine concentration
Free ropivacaine in plasma was assayed after ultrafiltration using Amicon Centrifree YM-30 centrifugal filter (Millipore, MA, USA). Aliquots of the ultrafiltrate (0.25 ml) were then extracted and analysed by HPLC as above. Ultrafiltrate ropivacaine concentrations were interpolated from a plot of peak height ratio (ropivacaine : bupivacaine) versus ropivacaine added to blank plasma ultrafiltrate (0–75 µg litre–1). The correlation coefficient over the range 15–75 µg litre–1 was 0.998. The coefficient of variation for the concentration range 15–75 µg litre–1 was between 2.6 and 7.4%, and the limit of quantification was 10 µg litre–1.

Pharmacokinetic analysis
A one-compartment model with sequential bolus and infusion inputs was fitted (unweighted) to the total plasma ropivacaine concentration–time data13 to give estimates of elimination half-life (t1/2), apparent total clearance (Clt/F) and apparent volume of distribution (Vd/F). Cmax (free and total) was defined as the highest concentration achieved during the time at which the infusion regimen had achieved a steady-state. The free fraction for ropivacaine in plasma (fµ) was calculated from measurements of three to seven different samples for each individual patient. Free ropivacaine clearance (Clf/F) was calculated as (Clt/F)/fµ.14

Statistical analysis
Patient characteristics and plasma (total and free) ropivacaine concentrations are summarized as mean (range), and fµ data (as percent) are summarized as median (range). Derived pharmacokinetic data are summarized as mean (95% CI). Correlation between age and pharmacokinetic parameters was investigated using linear regression analysis. Kruskal–Wallis one-way ANOVA was used to examine fµ across the six sampling times (1–48 h). A value of P<0.05 was considered significant.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Eighteen children (nine females) were included in the study (Table 1). Their mean age was 3.3 yr (0.3–7.3 yr) and mean weight was 15.5 kg (6–30 kg). The epidural catheter was inserted at a low thoracic level in seven and at a lumbar level in 11 children. The mean duration for the epidural infusion was 61.3 h (36–96 h). The mean sampling time was 49.3 h (24–96 h). In patient 9, the epidural catheter fell out after 40 h. In patient 12, the infusion was stopped after 48 h. However, 3 h later he experienced severe pain, which was treated with an 8-ml bolus of 0.2% ropivacaine followed by recommencement of the epidural ropivacaine infusion for an additional 24 h. No blood samples were taken from this child after this event.


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Table 1 Patient characteristics
 
Clinical efficacy
The epidural blocks obtained were considered successful in all the children, as they achieved adequate intra- and postoperative analgesia, and completed the study without complications or signs of clinical toxicity. None of the children required transfusion of blood or blood products.

Arterial pressure, pulse rate, respiratory rate and SpO2 remained stable throughout the study period in all children. Overall, pain scores were <3/10. Six patients were given one to four bolus doses of morphine during the first 24 h postoperatively, because of distress rather than pain. Patient 7 needed three bolus doses of morphine over a period of 24 h following the cessation (at 72 h) of the epidural ropivacaine infusion. Due to the age of patient 17 (3.5 months), the epidural ropivacaine infusion was stopped after 48 h and a morphine infusion comprising 10 µg kg–1 h–1 was initiated for a further 24 h.

When not asleep, all the patients had a sedation score <1. Four patients had a total of five episodes of postoperative nausea and vomiting which was alleviated by the administration of ondansetron. Patient 4 vomited intermittently throughout the entire study period despite the administration of ondansetron, metoclopramide and trimeprazine. Patients 5 and 14 had a motor block score of 2 for the first 24 h postoperatively and, after that, their motor block score increased to, and stayed at, 3 for the rest of the infusion period. The remaining 16 patients had a motor block score of 3 throughout the entire study period. None of the children suffered any pruritus. During the entire study period, patient 4 intermittently showed jerky movements of her legs when asleep.

Pharmacokinetic data
A one-compartment open model with an infusion input was fitted to the data for 15 patients. Figure 1AC shows plasma ropivacaine (total and free) concentration–time profiles for patients 6, 9 and 16 who were typical of the group. Data from three patients could not be analysed by the above method. Patient 4 (Fig. 1D) did not reach steady-state during the course of the study, and in patients 8 and 17 there were insufficient data points for a robust analysis.



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Fig 1 Plasma concentration–time profiles for total (•) and free ({blacksquare}) ropivacaine in patients 6 (A), 9 (B), 16 (C) and 4 (D). The solid lines show the computer-generated line of best fit for a one-compartment open model with an initial epidural ropivacaine bolus dose of 1 mg kg–1 over 10 min, followed by an epidural ropivacaine infusion of 0.4 mg kg–1 h–1. Patient 4 (D) did not reach steady-state and the pharmacokinetic model therefore could not be fitted to the data.

 
Mean (range) ropivacaine concentrations (total and free) and the median (range) % of free unbound ropivacaine from all the children studied are stated in Table 2. Total plasma ropivacaine concentrations were mainly low and within or below limits reported to be ‘safe’ in adults (1000–3000 µg litre–1).4 1522 In the majority of the children, concentrations had reached steady-state within 36 h. Mean (range) Cmax,total was 1202 µg litre–1 (312–3189 µg litre–1). The greatest individual total plasma ropivacaine concentration (3189 µg litre–1) was measured at 48 h. This patient (17) was the youngest in our group (3.5 months) and we deliberately did not want to continue the epidural ropivacaine infusion beyond 48 h in this infant. It is noteworthy, however, that steady-state was probably reached at ~ 36 h.


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Table 2 Total (Ct) and free (Cf) plasma ropivacaine concentrations (mean and range) and percent free unbound (fµ) for ropivacaine (median and range) at different time points during continuous epidural infusion in children
 
Free ropivacaine concentrations ranged from 10 to 56 µg litre–1. Mean (range) Cmax,free measured in each patient was 34 µg litre–1 (23–56 µg litre–1). The greatest individual free concentration of 56 µg litre–1 was measured 1 h after the initial ropivacaine bolus dose in patient 1. Overall, we found the highest free concentrations in this patient, though they tended to decrease with time.

Median plasma fµ for ropivacaine in 14 patients with three or more individual measurements varied over a twofold range. However, while there was a trend for fµ to be higher in the 1 h sample (median 5.2%), than in samples taken at later times (medians ranging from 2.1 to 3.3%), this was not statistically significant by ANOVA (P=0.068).

Pharmacokinetic parameters for the study are summarized in Table 3. Mean (95% CI) Vd/F for total ropivacaine was 3.1 litre kg–1 (2.1–4.2 litre kg–1), Clt/F was 8.5 ml kg–1 min–1 (5.8–11.1 ml kg–1 min–1) and t1/2 was 4.9 h (3.0–6.7 h). Clf/F was 220 ml kg–1 min–1 (170–270 ml kg–1 min–1). We were unable to demonstrate any correlation between age and any of the pharmacokinetic parameters.


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Table 3 Pharmacokinetic descriptors for ropivacaine pharmacokinetics following epidural infusion in children (data as mean ± 95% CI). Vd/F=volume of distribution/absorption, Kel=elimination constant, t1/2=elimination half-life, Clt/F=total clearance/bioavailability, Clf/F=free clearance/bioavailability, fµ=% free ropivacaine.
 

    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
This is the first study describing the pharmacokinetics of ropivacaine during long-term continuous epidural infusion in children. The dosage regimen used (0.4 mg kg–1 h–1 of 0.2% ropivacaine) was based on experience gained in a previous pharmacokinetic study of bolus caudal administration of ropivacaine in our hospital,10 and on a letter describing the use of epidural ropivacaine infusion in children.12 A constant infusion was chosen on the basis that it would produce stable analgesia and facilitate pharmacokinetic analysis of the data. Additional analgesia, if needed, was provided by i.v. morphine. In a normal clinical situation, other manoeuvres, such as increasing the infusion rate, administering bolus top-ups or co-administering epidural opioids would have been more appropriate, but this was precluded by our study design. It must be stressed that the aim of any continuous regional anaesthetic technique is to achieve adequate analgesia with the lowest possible plasma concentrations of any local anaesthetics.23

In general, pain scores were low, <3/10. Six children needed between one and four bolus doses of i.v. morphine (25 µg kg–1) during the first 24 postoperative hours, mainly because of a need to control distress or agitation rather than pain. Although it is possible that a higher initial bolus dose and/or co-administration of an epidural opioid would have minimized this problem, lack of sedation is a recognized problem in young children receiving epidural local anaesthetic infusion in the postoperative period.24 Two children needed morphine so that they could be weaned from the epidural ropivacaine infusion. One child had three bolus doses of morphine, and the other was given a morphine infusion (10 µg kg –1 h –1 for 24 h) following cessation of the ropivacaine infusion at 72 and 48 h, respectively.

Motor block was a minor problem; only two children had impaired motor function. In both of these children, motor block was seen only during the first 24 h. A major criticism of the Bromage motor scale is that it incorporates an assessment of degree of spread of local anaesthetic in addition to depth of motor block. However, it is simple to perform, easily graded and reproducible. The degree of sensory block was not measured in this study due to lack of an appropriate monitoring tool in young children. In addition, the problem of urinary retention induced by epidural ropivacaine could not be addressed in this study, as all children had a urinary catheter sited.

No adverse reactions that could have been related to ropivacaine were seen. Overall, both the total and free ropivacaine concentrations were comparable to those tolerated by adults (i.e. 1000–3000 µg litre–1 and 10–150 µg litre–1, respectively).4 1522 Total ropivacaine concentrations in our study varied between 102 and 3189 µg litre–1. The highest individual total ropivacaine concentration of 3189 µg litre–1 was measured at 48 h in the youngest child studied (3.5 months). In adults, total ropivacaine concentrations up to 5200 µg litre–1 have been tolerated during long-term epidural ropivacaine infusion.19 However, the toxicity of local anaesthetics is more closely related to the free plasma concentrations (as well as its rate of increase) rather than the total concentrations per se, as only the free drug can reach receptor sites.23 Free ropivacaine concentrations in our study varied between 10 and 56 µg litre–1. The highest individual free ropivacaine concentration of 56 µg litre–1 was found in a 6-month-old baby at 1 h following the initial bolus dose of 0.2% ropivacaine 1 mg kg–1 (i.e. before commencement of the infusion). The free concentrations in this child decreased over time during the epidural infusion, as was the case in most of the children studied.

Central nervous system toxicity has been seen in healthy adult volunteers at arterial free plasma concentrations of 340–850 µg litre–1 after rapid i.v. infusion of ropivacaine (10 mg min–1).4 Toxic concentrations estimated by peripheral venous free plasma concentrations seen after slow systemic input can be assumed to be similar to free arterial concentrations.4 19

In agreement with previous adult studies,19 22 the mean fµ for ropivacaine decreased slightly from 5.2% at 1 h to 2.1% at 48 h. This phenomenon has been suggested to be due to perioperative stress-induced increase in plasma {alpha}1-acid glycoprotein (AAG), the acute phase protein to which ropivacaine mainly binds.19 22 25 Up to 50% of the perioperative variation in fµ in adults can be explained by changes in the plasma concentrations of AAG.22 This figure may be even higher in neonates and infants in whom the plasma protein-binding capacity of AAG is significantly reduced, a well-known problem in neonates and infants when bupivacaine is used.2631 In order to minimize the amount of blood taken from the children in this study, we did not measure AAG concentrations.

Ropivacaine is predominantly eliminated by liver metabolism.32 It has an intermediate to low extraction ratio33 with the total plasma clearance dependent on fµ, and unbound plasma clearance almost exclusively dependent on hepatic enzymatic activity.19 22 Differences in fµ are thus likely to contribute significantly to inter-patient variability in overall clearance. However, in the present study, the time-related changes in fµ were relatively small and unlikely to cause major alterations in clearance during infusions of 2–4 days duration.

The mean apparent volume of Vd/F for total ropivacaine (3.1 litre kg–1) in this study was much greater than previously seen in adults (0.5 litre/kg),16 33 but similar to that recently reported in children aged 1–6 yr following a single caudal ropivacaine bolus dose (2.4 litre kg–1).10 The mean Clt for total ropivacaine in this study (8.5 ml kg–1 min–1) was only slightly higher than that following continuous epidural infusion (5.5–7.7 ml kg–1 min–1)16 18 2022 33 in adults or children (7.6 ml kg–1 min–1).10 11 The mean t1/2 obtained in this study (4.9 h) was in agreement with the majority of adult long-term epidural infusion studies,16 1820 but somewhat longer than recently reported in two paediatric caudal ropivacaine bolus dose studies (3.3–3.9 h).10 11

In conclusion, continuous epidural infusion of 0.2% ropivacaine in children aged 3.5 months to 8 yr at a rate of 0.4 mg kg–1 h–1 provides good analgesia with few side effects. However, in neonates and infants, this infusion rate should probably not be used for more than 36–48 h. Further studies into safety, efficacy and pharmacokinetics of ropivacaine in paediatrics are warranted, particularly in neonates and infants.


    Acknowledgement
 
We thank the Princess Margaret Hospital Department of Anaesthesia Research Fund for financial support.


    Footnotes
 
* Corresponding author: Department of Anaesthesia and Intensive Care, Odense University Hospital, DK-5000 Odense C, Denmark Back


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
1 McClure JH. Ropivacaine. Br J Anaesth 1996; 76: 300–7[Free Full Text]

2 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: 563–9[Abstract]

3 Plowman AN, Bolsin S, Mather LE. Central nervous system toxicity attributable to epidural ropivacaine hydrochloride. Anaesthesia Intens Care 1998; 26: 204–6

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

5 Ivani G, Mereto N, Lampugnani E, De Negri P, Torre M, Mattioli G, Jasonni V, Lönnqvist PA. Ropivacaine in paediatric surgery: preliminary results. Paediatr Anaesth 1998; 8: 127–9[ISI][Medline]

6 Ivani G, Mazzarello G, Lampugnani E, De Negri P, Torre M, Lönnqvist PA. Ropivacaine for central blocks in children. Anaesthesia 1998; 53: 74–6

7 Ivani G, Lampugnani E, Torre M, Calevo Maria G, De Negri P, Borrometi F, Messeri A, Calamandrei M, Lönnqvist PA, Morton NS. Comparison of ropivacaine with bupivacaine for paediatric caudal block. Br J Anaesth 1998; 81: 247–8[Abstract/Free Full Text]

8 Da Conceicao MJ, Coelho L, Khalil M. Ropivacaine 0.25% compared with bupivacaine 0.25% by the caudal route. Paediatr Anaesth 1999; 9: 229–33[ISI][Medline]

9 Koinig H, Krenn CG, Glaser C, Marhofer P, Wildling E, Brunner M, Wallner T, Grabner C, Klimscha W, Semsroth M. The dose response of caudal ropivacaine in children. Anesthesiology 1999; 90: 1339–44[ISI][Medline]

10 Habre W, Bergesio R, Johnson C, Hackett P, Joyce D, Sims C. Pharmacokinetics of ropivacaine following caudal analgesia in children. Paediatr Anaesth 2000; 10: 143–7[ISI][Medline]

11 Lönnqvist PA, Westrin P, Larsson BA, Olsson GL, Huledal G. Ropivacaine pharmacokinetics following paediatric caudal block: preliminary results. European Society for Regional Anaesthesia and European Meeting, Geneva Switzerland, September 1998. IMRA 1998; 10: 65 (Abstract)

12 Moriarty A. Use of ropivacaine in postoperative infusions (letter). Paediatr Anaesth 1997; 7: 478

13 Heinzel G, Woloszak R, Thomann P. In: Pharmacokinetic and Pharmacodynamic Data Analysis System for the PC. Stuttgart: Gustav Fischer, 1993; Topfit Version 2.0

14 Gibaldi M. Compartmental and non-compartmental pharmacokinetics. In: Gibaldi M, ed. Biopharmaceutics and Clinical Pharmacokinetics, 4th edn. Philadelphia PA, Lea & Febiger 1991; 23

15 Morton CP, Bloomfield S, Magnusson A, Jozwiak H, McClure JH. Ropivacaine 0.75% for extradural anaesthesia in elective Caesarian section: an open clinical and pharmacokinetic study in mother and neonate. Br J Anaesth 1997; 79: 3–8[Abstract/Free Full Text]

16 Emanuelsson B-M, 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]

17 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]

18 Morrison LMM, Emanuelsson BM, McClure JH, Pollock AJ, McKeown DW, Brockway M, Wildsmith JAW. Efficacy and kinetics of extradural ropivacaine: comparison with bupivacaine. Br J Anaesth 1994; 72: 164–9[Abstract]

19 Scott DA, Emanuelsson B-M, 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]

20 Sandler AN, Arlander E, Finucane BT, Taddio A, Chan V, Milner A, Callahan SO, Friedlander M, Muzyka D. Pharmacokinetics of three doses of epidural ropivacaine during hysterectomy and comparison with bupivacaine. Can J Anaesth 1998; 45: 843–9[Abstract]

21 Katz JA, Bridenbaugh PO, Knarr DC, Helton SH, Denson DD. Pharmacodynamics and pharmacokinetics of epidural ropivacaine in humans. Anesth Analg 1990; 70: 16–21[Abstract]

22 Erichsen CJ, Sjövall J, Kehlet 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]

23 Berde CB. Toxicity of local anesthetics in infants and children. J Pediatr 1993; 122: 14–20

24 Wolf AR, Hughes DG. Pain relief for infants undergoing abdominal surgery: comparison of infusions of i.v. morphine and extradural bupivacaine. Br J Anaesth 1993; 70: 10–6[Abstract]

25 Booker PD, Taylor C, Saba G. Perioperative changes in {alpha}1-acid glycoprotein concentration in infants undergoing major surgery. Br J Anaesth 1996; 76: 365–8[Abstract/Free Full Text]

26 Peutrell JM, Holder K, Gregory M. Plasma bupivacaine concentrations associated with extradural infusions in babies. Br J Anaesth 1997; 78: 160–2[Abstract/Free Full Text]

27 Cheung SLW, Booker PD, Franks R, Pozzi M. Serum concentrations of bupivacaine during prolonged continuous paravertebral infusion in young infants. Br J Anaesth 1997; 79: 9–13[Abstract/Free Full Text]

28 Larsson BA, Lönnquist PA, Olsson GL. Plasma concentrations of bupivacaine in neonates after continuous epidural infusion. Anesth Analg 1997; 84: 501–5[Abstract]

29 Smith T, Moratin P, Wulf H. Smaller children have greater bupivacaine concentrations after ilioinguinal block. Br J Anaesth 1996; 76: 452–5[Abstract/Free Full Text]

30 Larsson BA, Olsson GL, Lönnqvist PA. Plasma concentrations of bupivacaine in young infants after continuous epidural infusion. Paediatr Anaesth 1994; 4: 159–62

31 Beauvoir C, Rochette A, Desch G, d’Athis F. Spinal anaesthesia in newborns: total and free bupivacaine concentrations. Paediatr Anaesth 1996; 6: 195–9[ISI][Medline]

32 Halldin MM, Bredberg E, Angelin B, Arvidsson T, Askemark Y, Elofsson S, Widman M. Metabolism and excretion of ropivacaine in humans. Drug Metab Dispos 1996; 24: 962–8

33 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]