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
This article is acompanied by Editorial II.
Accepted for publication: December 12, 1999
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Br J Anaesth 2000; 85: 34753
Keywords: anaesthetics, local; anaesthetic techniques, epidural; paediatric pharmacokinetics
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
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 |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
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) kg1 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 kg1 h1. No extra bolus doses were allowed. Paracetamol 1520 mg kg1 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 kg1 was given. Intraoperative fluid management comprised Ringers lactate at a rate of 510 ml kg1 h1.
Postoperatively, all children were monitored according to a protocol comprising hourly recording of pulse and respiratory rates, SpO2, observational pain score (numerical 010), 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 (1.52 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 (12 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 (01200 µg litre1). The correlation coefficient over the concentration range 100800 µg litre1 was 0.9999. The coefficient of variation over the concentration range 150700 µg litre1 was between 1.5 and 2.5%, and the limit of quantification was 10 µg litre1. 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 (075 µg litre1). The correlation coefficient over the range 1575 µg litre1 was 0.998. The coefficient of variation for the concentration range 1575 µg litre1 was between 2.6 and 7.4%, and the limit of quantification was 10 µg litre1.
Pharmacokinetic analysis
A one-compartment model with sequential bolus and infusion inputs was fitted (unweighted) to the total plasma ropivacaine concentrationtime data13 to give estimates of elimination half-life (t), 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. KruskalWallis one-way ANOVA was used to examine fµ across the six sampling times (148 h). A value of P<0.05 was considered significant.
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
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 kg1 h1 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) concentrationtime 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.
|
|
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 kg1 (2.14.2 litre kg1), Clt/F was 8.5 ml kg1 min1 (5.811.1 ml kg1 min1) and t was 4.9 h (3.06.7 h). Clf/F was 220 ml kg1 min1 (170270 ml kg1 min1). We were unable to demonstrate any correlation between age and any of the pharmacokinetic parameters.
|
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
In general, pain scores were low, <3/10. Six children needed between one and four bolus doses of i.v. morphine (25 µg kg1) 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. 10003000 µg litre1 and 10150 µg litre1, respectively).4 1522 Total ropivacaine concentrations in our study varied between 102 and 3189 µg litre1. The highest individual total ropivacaine concentration of 3189 µg litre1 was measured at 48 h in the youngest child studied (3.5 months). In adults, total ropivacaine concentrations up to 5200 µg litre1 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 litre1. The highest individual free ropivacaine concentration of 56 µg litre1 was found in a 6-month-old baby at 1 h following the initial bolus dose of 0.2% ropivacaine 1 mg kg1 (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 340850 µg litre1 after rapid i.v. infusion of ropivacaine (10 mg min1).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 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 24 days duration.
The mean apparent volume of Vd/F for total ropivacaine (3.1 litre kg1) 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 16 yr following a single caudal ropivacaine bolus dose (2.4 litre kg1).10 The mean Clt for total ropivacaine in this study (8.5 ml kg1 min1) was only slightly higher than that following continuous epidural infusion (5.57.7 ml kg1 min1)16 18 2022 33 in adults or children (7.6 ml kg1 min1).10 11 The mean t 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 (3.33.9 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 kg1 h1 provides good analgesia with few side effects. However, in neonates and infants, this infusion rate should probably not be used for more than 3648 h. Further studies into safety, efficacy and pharmacokinetics of ropivacaine in paediatrics are warranted, particularly in neonates and infants.
![]() |
Acknowledgement |
---|
![]() |
Footnotes |
---|
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
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: 5639[Abstract]
3 Plowman AN, Bolsin S, Mather LE. Central nervous system toxicity attributable to epidural ropivacaine hydrochloride. Anaesthesia Intens Care 1998; 26: 2046
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: 50714
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: 1279[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: 746
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: 2478
8 Da Conceicao MJ, Coelho L, Khalil M. Ropivacaine 0.25% compared with bupivacaine 0.25% by the caudal route. Paediatr Anaesth 1999; 9: 22933[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: 133944[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: 1437[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: 38
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: 130917[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: 55862
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: 1649[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: 132230[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: 8439[Abstract]
21 Katz JA, Bridenbaugh PO, Knarr DC, Helton SH, Denson DD. Pharmacodynamics and pharmacokinetics of epidural ropivacaine in humans. Anesth Analg 1990; 70: 1621[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: 83442[ISI][Medline]
23 Berde CB. Toxicity of local anesthetics in infants and children. J Pediatr 1993; 122: 1420
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: 106[Abstract]
25 Booker PD, Taylor C, Saba G. Perioperative changes in 1-acid glycoprotein concentration in infants undergoing major surgery. Br J Anaesth 1996; 76: 3658
26 Peutrell JM, Holder K, Gregory M. Plasma bupivacaine concentrations associated with extradural infusions in babies. Br J Anaesth 1997; 78: 1602
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: 913
28 Larsson BA, Lönnquist PA, Olsson GL. Plasma concentrations of bupivacaine in neonates after continuous epidural infusion. Anesth Analg 1997; 84: 5015[Abstract]
29 Smith T, Moratin P, Wulf H. Smaller children have greater bupivacaine concentrations after ilioinguinal block. Br J Anaesth 1996; 76: 4525
30 Larsson BA, Olsson GL, Lönnqvist PA. Plasma concentrations of bupivacaine in young infants after continuous epidural infusion. Paediatr Anaesth 1994; 4: 15962
31 Beauvoir C, Rochette A, Desch G, dAthis F. Spinal anaesthesia in newborns: total and free bupivacaine concentrations. Paediatr Anaesth 1996; 6: 1959[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: 9628
33 Lee A, Fagan, D, Lamont M, Tucker GT, Halldin M, Scott DB. Disposition kinetics of ropivacaine in humans. Anesth Analg 1989; 69: 7368[Abstract]