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Pharmacokinetics and clinical efficacy of long-term epidural ropivacaine infusion in children †

2000; Elsevier BV; Volume: 85; Issue: 3 Linguagem: Inglês

10.1093/bja/85.3.347

1471-6771

Tom G. Hansen, Kenneth F. Ilett, S.I. Lim, C. Reid, L. Peter Hackett, R. Bergesio,

Nausea and vomiting management

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−1h−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). 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−1h−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). 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.1McClure JH Ropivacaine.Br J Anaesth. 1996; 76: 300-307Crossref PubMed Scopus (425) Google Scholar, 2Scott DB Lee A Fagan D Bowler GMR Bloomfield P Lundh R Acute toxicity of ropivacaine compared with that of bupivacaine.Anesth Analg. 1989; 69: 563-569Crossref PubMed Scopus (651) Google Scholar, 3Plowman AN Bolsin S Mather LE Central nervous system toxicity attributable to epidural ropivacaine hydrochloride.Anaesthesia Intens Care. 1998; 26: 204-206PubMed Google Scholar, 4Knudsen 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: 507-514Crossref PubMed Scopus (793) Google Scholar 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.5Ivani 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: 127-129Crossref PubMed Scopus (95) Google Scholar, 6Ivani G Mazzarello G Lampugnani E De Negri P Torre M Lönnqvist PA Ropivacaine for central blocks in children.Anaesthesia. 1998; 53: 74-76Crossref PubMed Scopus (22) Google Scholar, 7Ivani 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: 247-248Crossref PubMed Scopus (108) Google Scholar, 8Da Conceicao MJ Coelho L Khalil M Ropivacaine 0.25% compared with bupivacaine 0.25% by the caudal route.Paediatr Anaesth. 1999; 9: 229-233Crossref PubMed Google Scholar, 9Koinig 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: 1339-1344Crossref PubMed Scopus (86) Google Scholar, 10Habre W Bergesio R Johnson C Hackett P Joyce D Sims C Pharmacokinetics of ropivacaine following caudal analgesia in children.Paediatr Anaesth. 2000; 10: 143-147Crossref PubMed Scopus (45) Google Scholar, 11Lönnqvist 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 (Abstract): 65Google Scholar The concept of epidural ropivacaine infusion in children has been addressed in a letter,12Moriarty A Use of ropivacaine in postoperative infusions (letter).Paediatr Anaesth. 1997; 7: 478PubMed Google Scholar 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. After approval by the Princess Margaret Hospital Ethics Committee and written informed parental consent, 18 children (ASA I–II, age >3 months, 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. 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. 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 (250×4 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. 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. A one-compartment model with sequential bolus and infusion inputs was fitted (unweighted) to the total plasma ropivacaine concentration–time data13Heinzel G Woloszak R Thomann P Pharmacokinetic and Pharmacodynamic Data Analysis System for the PC. Gustav Fischer, Stuttgart1993Google Scholar to give estimates of elimination half-life (t½), 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.14Gibaldi M Compartmental and non-compartmental pharmacokinetics.in: Gibaldi M Biopharmaceutics and Clinical Pharmacokinetics. 4th edn. Lea & Febiger, Philadelphia PA1991: 23Google Scholar 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. 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.Table 1Patient characteristicsPatient no.Age (yr)GenderWeight (kg)SurgeryDuration of infusion (h)10.6M9.0pyeloplasty3624.6M13.5r/o osteoid osteoma femur4833.4M17.5ureteric reimplantation7242.3F13.5ureteric reimplantation4853.4F14.5r/o Wilm's tumour7267.2F30.0ureteric reimplantation7271.8M15.0r/o Wilm's tumour7283.7F14.5pyeloplasty4891.8F12.5nephrectomy36104.0F18.5ureteric reimplantation96115.5F16.0ureteric reimplantation92127.3M26.0pyeloplasty76131.5F10.0vaginoplasty48146.4F24.4ureteric reimplantation72150.8M10.0ureteric reimplantation48163.1M18.0ureteric reimplantation72170.3M6.0Duhamel's pull-through48181.7M10.5ureteric reimplantation48 Open table in a new tab 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. A one-compartment open model with an infusion input was fitted to the data for 15 patients. Figure 1a–c 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. 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).4Knudsen 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: 507-514Crossref PubMed Scopus (793) Google Scholar 15Morton 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: 3-8Crossref PubMed Scopus (45) Google Scholar, 16Emanuelsson 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: 1309-1317Crossref PubMed Scopus (58) Google Scholar, 17McCrae 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: 558-562Crossref PubMed Scopus (32) Google Scholar, 18Morrison 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: 164-169Crossref PubMed Scopus (116) Google Scholar, 19Scott 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: 1322-1330Crossref PubMed Google Scholar, 20Sandler 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: 843-849Crossref PubMed Scopus (13) Google Scholar, 21Katz JA Bridenbaugh PO Knarr DC Helton SH Denson DD Pharmacodynamics and pharmacokinetics of epidural ropivacaine in humans.Anesth Analg. 1990; 70: 16-21Crossref PubMed Scopus (82) Google Scholar, 22Erichsen 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: 834-842Crossref PubMed Scopus (80) Google Scholar 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.Table 2Total (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 childrenHours after start016122436487296Ct< 5408619809106311091077925933(μg litre−1)(102–719)(149–1256)(298–1638)(312–2329)(392–3167)(204–3189)(690–1277)—Cf—21262628292722—(μg litre−1)(10–56)(10–54)(12–48)(16–47)(17–51)(17–52)(14–29)fμ—5.23.32.52.82.72.1—(1.9–12.9)(1.6–10.2)(1.4–8.4)(1.4–5.7)(1.6–8.5)(1.6–4.0)(2.0–3.8) Open table in a new tab 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 t½ 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.Table 3Pharmacokinetic descriptors for ropivacaine pharmacokinetics following epidural infusion in children (data as mean ± 95% CI). Vd/F=volume of distribution/absorption, Kel=elimination constant, t½=elimination half-life, Clt/F=total clearance/bioavailability, Clf/F=free clearance/bioavailability, fμ=% free ropivacaine.Pharmacokinetic dataVd/F (litre kg−1)Kel (h−1)t½ (h)Clt/F (ml kg−1 min−1)fμ (%)Clf/F (ml kg−1 min−1)3.10.2334.98.54.2220(2.1–4.2)(0.133–0.333)(3.0–6.7)(5.8–11.1)(2.7–5.7)(170–270) Open table in a new tab 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,10Habre W Bergesio R Johnson C Hackett P Joyce D Sims C Pharmacokinetics of ropivacaine following caudal analgesia in children.Paediatr Anaesth. 2000; 10: 143-147Crossref PubMed Scopus (45) Google Scholar and on a letter describing the use of epidural ropivacaine infusion in children.12Moriarty A Use of ropivacaine in postoperative infusions (letter).Paediatr Anaesth. 1997; 7: 478PubMed Google Scholar 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.23Berde CB Toxicity of local anesthetics in infants and children.J Pediatr. 1993; 122: 14-20Abstract Full Text PDF PubMed Scopus (116) Google Scholar 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.24Wolf 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: 10-16Crossref PubMed Scopus (60) Google Scholar 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).4Knudsen 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: 507-514Crossref PubMed Scopus (793) Google Scholar 15Morton 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: 3-8Crossref PubMed Scopus (45) Google Scholar, 16Emanuelsson 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: 1309-1317Crossref PubMed Scopus (58) Google Scholar, 17McCrae 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: 558-562Crossref PubMed Scopus (32) Google Scholar, 18Morrison 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: 164-169Crossref PubMed Scopus (116) Google Scholar, 19Scott 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: 1322-1330Crossref PubMed Google Scholar, 20Sandler 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: 843-849Crossref PubMed Scopus (13) Google Scholar, 21Katz JA Bridenbaugh PO Knarr DC Helton SH Denson DD Pharmacodynamics and pharmacokinetics of epidural ropivacaine in humans.Anesth Analg. 1990; 70: 16-21Crossref PubMed Scopus (82) Google Scholar, 22Erichsen 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: 834-842Crossref PubMed Scopus (80) Google Scholar 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.19Scott 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: 1322-1330Crossref PubMed Google Scholar 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.23Berde CB Toxicity of local anesthetics in infants and children.J Pediatr. 1993; 122: 14-20Abstract Full Text PDF PubMed Scopus (116) Google Scholar 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).4Knudsen 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: 507-514Crossref PubMed Scopus (793) Google Scholar Toxic concentrations estimated by peripheral venous free plasma concentrations seen after slow systemic input can be assumed to be similar to free arterial concentrations.4Knudsen 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: 507-514Crossref PubMed Scopus (793) Google Scholar 19Scott 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: 1322-1330Crossref PubMed Google Scholar In agreement with previous adult studies,19Scott 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: 1322-1330Crossref PubMed Google Scholar 22Erichsen 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: 834-842Crossref PubMed Scopus (80) Google Scholar 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 α1-acid glycoprotein (AAG), the acute phase protein to which ropivacaine mainly binds.19Scott 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: 1322-1330Crossref PubMed Google Scholar 22Erichsen 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: 834-842Crossref PubMed Scopus (80) Google Scholar 25Booker PD Taylor C Saba G Perioperative changes in α1-acid glycoprotein concentration in infants undergoing major surgery.Br J Anaesth. 1996; 76: 365-368Crossref PubMed Scopus (90) Google Scholar Up to 50% of the perioperative variation in fμ in adults can be explained by changes in the plasma concentrations of AAG.22Erichsen 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: 834-842Crossref PubMed Scopus (80) Google Scholar 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.26Peutrell JM Holder K Gregory M Plasma bupivacaine concentrations associated with extradural infusions in babies.Br J Anaesth. 1997; 78: 160-162Crossref PubMed Scopus (25) Google Scholar, 27Cheung SLW Booker PD Franks R Pozzi M Serum concentrations of bupivacaine during prolonged continuous paravertebral infusion in young infants.Br J Anaesth. 1997; 79: 9-13Crossref PubMed Scopus (50) Google Scholar, 28Larsson BA Lönnquist PA Olsson GL Plasma concentrations of bupivacaine in neonates after continuous epidural infusion.Anesth Analg. 1997; 84: 501-505PubMed Google Scholar, 29Smith T Moratin P Wulf H Smaller children have greater bupivacaine concentrations after ilioinguinal block.Br J Anaesth. 1996; 76: 452-455Crossref PubMed Scopus (53) Google Scholar, 30Larsson BA Olsson GL Lönnqvist PA Plasma concentrations of bupivacaine in young infants after continuous epidural infusion.Paediatr Anaesth. 1994; 4: 159-162Crossref Scopus (24) Google Scholar, 31Beauvoir C Rochette A Desch G d’Athis F Spinal anaesthesia in newborns: total and free bupivacaine concentrations.Paediatr Anaesth. 1996; 6: 195-199Crossref PubMed Scopus (29) Google Scholar 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.32Halldin 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: 962-968PubMed Google Scholar It has an intermediate to low extraction ratio33Lee A Fagan D Lamont M Tucker GT Halldin M Scott DB Disposition kinetics of ropivacaine in humans.Anesth Analg. 1989; 69: 736-738Crossref PubMed Scopus (127) Google Scholar with the total plasma clearance dependent on fμ, and unbound plasma clearance almost exclusively dependent on hepatic enzymatic activity.19Scott 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: 1322-1330Crossref PubMed Google Scholar 22Erichsen 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: 834-842Crossref PubMed Scopus (80) Google Scholar 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),16Emanuelsson 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: 1309-1317Crossref PubMed Scopus (58) Google Scholar 33Lee A Fagan D Lamont M Tucker GT Halldin M Scott DB Disposition kinetics of ropivacaine in humans.Anesth Analg. 1989; 69: 736-738Crossref PubMed Scopus (127) Google Scholar but similar to that recently reported in children aged 1–6 yr following a single caudal ropivacaine bolus dose (2.4 litre kg−1).10Habre W Bergesio R Johnson C Hackett P Joyce D Sims C Pharmacokinetics of ropivacaine following caudal analgesia in children.Paediatr Anaesth. 2000; 10: 143-147Crossref PubMed Scopus (45) Google Scholar 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)16Emanuelsson 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: 1309-1317Crossref PubMed Scopus (58) Google Scholar 18Morrison 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: 164-169Crossref PubMed Scopus (116) Google Scholar 20Sandler 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: 843-849Crossref PubMed Scopus (13) Google Scholar, 21Katz JA Bridenbaugh PO Knarr DC Helton SH Denson DD Pharmacodynamics and pharmacokinetics of epidural ropivacaine in humans.Anesth Analg. 1990; 70: 16-21Crossref PubMed Scopus (82) Google Scholar, 22Erichsen 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: 834-842Crossref PubMed Scopus (80) Google Scholar 33Lee A Fagan D Lamont M Tucker GT Halldin M Scott DB Disposition kinetics of ropivacaine in humans.Anesth Analg. 1989; 69: 736-738Crossref PubMed Scopus (127) Google Scholar in adults or children (7.6 ml kg−1 min−1).10Habre W Bergesio R Johnson C Hackett P Joyce D Sims C Pharmacokinetics of ropivacaine following caudal analgesia in children.Paediatr Anaesth. 2000; 10: 143-147Crossref PubMed Scopus (45) Google Scholar 11Lönnqvist 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 (Abstract): 65Google Scholar The mean t½ obtained in this study (4.9 h) was in agreement with the majority of adult long-term epidural infusion studies,16Emanuelsson 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: 1309-1317Crossref PubMed Scopus (58) Google Scholar 18Morrison 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: 164-169Crossref PubMed Scopus (116) Google Scholar, 19Scott 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: 1322-1330Crossref PubMed Google Scholar, 20Sandler 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: 843-849Crossref PubMed Scopus (13) Google Scholar but somewhat longer than recently reported in two paediatric caudal ropivacaine bolus dose studies (3.3–3.9 h).10Habre W Bergesio R Johnson C Hackett P Joyce D Sims C Pharmacokinetics of ropivacaine following caudal analgesia in children.Paediatr Anaesth. 2000; 10: 143-147Crossref PubMed Scopus (45) Google Scholar 11Lönnqvist 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 (Abstract): 65Google Scholar 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−1h−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. We thank the Princess Margaret Hospital Department of Anaesthesia Research Fund for financial support.