1Department of Paediatric Anaesthesia and Intensive Care, KS/Astrid Lindgrens Childrens Hospital, Stockholm, Sweden. 2Department of Anaesthesia and Intensive Care, Lund University Hospital, Lund, Sweden. 3AstraZeneca R&D, Södertälje, Sweden
Accepted for publication: April 28, 2000
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Abstract |
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Br J Anaesth 2000; 85: 50611
Keywords: anaesthesia, paediatric; anaesthetic techniques, regional; anaesthetic techniques, epidural; analgesia, postoperative; anaesthetics, local; ropivacaine; pharmacokinetics
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Introduction |
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The primary aim of the present study was to investigate the pharmacokinetics of ropivacaine after caudal administration in children. A dose of 2 mg kg1 was chosen on the basis of the experience of ropivacaine in adults and the doses of bupivacaine used in this age group. Secondary aims were to assess postoperative analgesia and motor block and to document any adverse reactions.
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Materials and methods |
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Anaesthesia
Patients were premedicated with midazolam rectally (0.30.45 mg kg1) or i.v. (0.1 mg kg1). Eutectic mixture of local anaesthetics (EMLA®, Astra Zeneca, Södertälje, Sweden) was used to prevent pain from the insertion of an intravenous catheter. Anaesthesia was induced by thiopentone 510 mg kg1 i.v. and maintained by sevoflurane, nitrous oxide and oxygen. Airway management consisted of a face mask, laryngeal mask airway or endotracheal intubation, depending on the type of surgery and the expected duration of surgical intervention. For endotracheal intubation, adequate muscle relaxation was achieved by administration of atracurium 0.5 mg kg1 i.v. or suxamethonium 2.0 mg kg1 i.v. After induction of anaesthesia, a second intravenous cannula was inserted, for use for blood sampling only. The patient was then placed on their side and a caudal block with ropivacaine 2 mg ml1, 1 ml kg1, was performed. Ropivacaine was injected in fractions over 2 min. During anaesthesia, patients were monitored by ECG, pulse oximetry, capnography and non-invasive measurements of arterial pressure and inhalational agents. Opioids were avoided before or during surgery. However, according to our routine practice, all patients received paracetamol (total daily dose
100 mg kg1).
Blood and urine sampling
Peripheral venous blood samples (1 ml) for analysis of total plasma ropivacaine concentrations were collected from indwelling intravenous catheters immediately before and 15, 30, 60 min and 2, 4, 8 and 1236 h after administration of caudal ropivacaine. Free ropivacaine and 1-acid glycoprotein (AAG) concentrations were determined in the 30 min and 8 h samples, when larger volumes of blood (5 ml) were collected. The blood samples were centrifuged within 60 min of collection and the plasma was frozen at 20°C until assay.
In patients requiring urinary catheterization as a routine part of the surgical procedure, urine was collected for the determination of ropivacaine and its main metabolites, 3-hydroxyropivacaine and 2',6'-pipecoloxylidide (PPX). Urine was collected every 6 h for 36 h postoperatively or until the urinary catheter was removed. The volume of urine collected at each occasion was recorded and 5 ml samples were frozen at 20°C until assay.
Bioanalytical methods
The total concentration of ropivacaine base (relative molecular mass 274) in plasma was determined by a gas-chromatographic method with nitrogen-sensitive detection.6 The limit of quantification was optimized to 0.003 mg litre1 using 100 µl of plasma. The between-day coefficients of variation (CV) were <10% at concentrations in the range 0.00552.19 mg litre1. The accuracy was 99101%. The free concentration of ropivacaine base in plasma was determined using a coupled-column, liquid-chromatographic system with UV detection after ultrafiltration of plasma at pH 7.4 and 37°C.7 The limit of quantification was 0.003 mg litre1 using 1.0 ml of plasma. The between-day CV was 8.2% at a free ropivacaine concentration of 0.055 mg litre1. The concentration of AAG in plasma was determined by an immunoturbidometric method from Boehringer Mannheim. The limit of quantification was 0.12 g litre1 using 50 µl of plasma. The method was linear up to 5.33 g litre1. The between-day CV was 7% at 0.8 g litre1.
A new method was introduced for quantifying ropivacaine, 3-hydroxyropivacaine and PPX in urine. In previous studies, the concentration of ropivacaine and its main metabolites has been determined by a method based on liquid chromatography and UV detection.8 In the present study, some patients were treated with trimethoprim, which was co-determined with 3-hydroxyropivacaine using unselective UV detection. A new method based on a selective detection technique, tandem mass spectrometry, was used in the present study. As before, the concentrations of ropivacaine, 3-hydroxyropivacaine (relative molecular mass 290) and PPX (relative molecular mass 232) in urine were determined after acid hydrolysis with 6 M hydrochloric acid. This gives the sum of the conjugated and the unconjugated 3-hydroxyropivacaine, while ropivacaine and PPX exist only in the unconjugated form. A urine volume of 1.0 ml was used. Solid-phase extraction was used for sample preparation. The new selective liquid-chromatographic method with gradient elution and electrospray tandem mass spectrometry was used for the determination of ropivacaine, 3-hydroxyropivacaine and PPX in urine. The gradient system contained acetonitrile and ammonium formate buffer, pH 4. The scan mode was multiple reaction monitoring using the precursor ions at m/z, M+1, 275.2 for ropivacaine, 291.1 for 3-hydroxyropivacaine and 233.2 for PPX. After collisional dissociation the product ions were used for quantification, m/z, 126.0 for ropivacaine and 3-hydroxyropivacaine and 84.0 for PPX. The limit of quantification was 0.08 mg litre1 for ropivacaine, 0.49 mg litre1 for 3-hydroxyropivacaine and 0.18 mg litre1 for PPX. The between-day CVs were <5% at ropivacaine concentrations of 0.154.6 mg litre1. For 3-hydroxyropivacaine, the between-day CVs were <8% at concentrations of 0.9930 mg litre1 and for PPX they were <6% at concentrations of 0.4211 mg litre1. The accuracy was 97101%.
Pharmacokinetic calculations
The plasma concentrationtime data were analysed by non-compartmental methods using the pharmacokinetic program WinNonlin Professional version 2.0 (Pharsight Co., Mountain View, CA, USA). Peak plasma concentration (Cmax) and the time to Cmax (tmax) were obtained directly from the observed data. The free fraction of ropivacaine (fu) in a sample was calculated as free concentration divided by total concentration and the free ropivacaine concentration at tmax (Cu max) was estimated from Cmax and fu 30 min, assuming the protein binding to be equal at 30 min and at tmax. The terminal half-life (t1/2) was calculated by linear regression of the data points in the declining and linear part of the log-linear plasma concentrationtime curve. The area under the plasma concentrationtime profile up to infinity (AUC) was calculated using the linear trapezoidal rule up to the last blood sample and extrapolated to infinity by multiplying the concentration in the last measurable plasma concentration by t/ln2. The volume of distribution at steady state (Vss) was calculated as dose x (AUMC)/AUC2, where AUMC is the area under the first momenttime curve. Plasma clearance (Cl) was calculated as dose/AUC. Since the absorption of ropivacaine can be assumed to be complete after caudal administration, Vss and Cl are not been presented as apparent parameters. Cl for the unbound concentration (Clu) was calculated as Cl/fu 30 min and volume of distribution at steady state for the unbound fraction (Vss u) was calculated as Vss/fu 30 min. The hepatic extraction ratio (EH) of ropivacaine was calculated as blood clearance divided by the liver blood flow (QH). The blood:plasma concentration ratio of ropivacaine was assumed to be similar to adult values (0.7), since the plasma protein binding of ropivacaine and the haematocrit have reached adult values in the age group studied.9 10 QH was estimated from the adult value of liver blood flow, 1350 ml min1, adjusted to the individual body-surface area calculated as (weight (kg)/70 kg)0.7x1.8.11 The half-lives of 3-hydroxyropivacaine and PPX were estimated by linear regression of the linear and declining part of the log-linear plot of the excretion ratetime curve.
Clinical assessments
Postoperative analgesia and lower-limb motor function were assessed by the research staff at regular intervals, every hour during the first 8 h and then once within the interval 1236 h. Postoperative pain was assessed using a four-point behaviour observer scale (no pain, mild pain, moderate pain, severe pain).12 Supplemental opioid analgesia was administered if the pain was judged to be moderate or severe or the effect was considered insufficient by the research staff. The time to the first administration of opioid was recorded. Motor function was assessed as motor block present (inability to move the legs with slight stimulation allowed) or absent. Adverse events were recorded during the study period up to a telephone follow-up 2 weeks after surgery.
Statistical methods
The data were analysed using descriptive methods such as summary statistics and graphs. Possible relationships between variables were investigated using parametric linear regression. The results are presented as mean (SD) unless otherwise stated.
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Results |
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Discussion |
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Since the registration of ropivacaine for use in adults, a limited number of clinical studies have been published regarding the use of this new local anaesthetic in children.35 Caudal or epidural administration of ropivacaine 2 mg kg1 has been reported to be comparable to bupivacaine 2.02.5 mg kg1.3 Analgesia is significantly longer when using ropivacaine 5 mg ml1 (3.75 mg kg1) than with either ropivacaine or bupivacaine 2.5 mg ml1 (1.875 mg kg1).13 Where 2.53.75 mg ml1 solutions of bupivacaine and ropivacaine were used, ropivacaine administration was associated with a shorter duration of motor block.14 15
In the present study, the highest estimated individual peak plasma concentration of unbound ropivacaine was 0.043 mg litre1 (mean 0.024 mg litre1) and the mean Cmax of total ropivacaine was 0.47 mg litre1, which corresponds with previous data where single caudal doses of 1.875 mg kg1 produced a Cmax of c.0.6 mg litre1 in 5 yr old children.13 tmax, which tended to be shorter in older children, was within the range normally observed in adults.16 The acute tolerability of ropivacaine has been studied in healthy adult subjects. A threshold for central nervous system toxicity was apparent at mean (minimummaximum) unbound arterial plasma concentrations of ropivacaine of the order of 0.6 (0.30.9) mg litre1.1 Consequently, in the present study, the plasma concentrations of unbound ropivacaine were well below the threshold levels for toxicity in adults. AAG concentrations were similar 30 min and 8 h after caudal block and within ranges normally observed in healthy adult subjects17 and in 15 yr old (ASA III) patients.18 The free fraction of ropivacaine was in the range 311%, which is similar to the free fraction (6±1%) in adult patients 79 h after the start of an epidural infusion.19 There was no apparent age-dependency in bodyweight-adjusted volume of distribution (mean 2.4 litres kg1). However, it was larger than the corresponding value in adults (0.7 litres kg1).20
Bodyweight-adjusted clearance was the same as in adults (5 ml min1 kg1)20, without any apparent age-dependency. When estimating the hepatic extraction ratio in the present study, the hepatic blood flow was adjusted for body surface area, since hepatic blood flow in children correlates better with body surface area than with bodyweight.11 The hepatic blood flows found in the present study correspond to values obtained by duplex Doppler ultrasound measurements in this age group.21 Even if the estimation of the hepatic extraction ratio is based on assumptions, these are reasonable, and the extraction ratio value indicates that ropivacaine is handled as a drug with low to intermediate extraction characteristics by the liver, as in adults.9 Consequently, ropivacaine clearance is expected to depend on the unbound fraction of ropivacaine rather than on the liver blood flow.
In the present study, the metabolic pattern of the main metabolites, 3-hydroxyropivacaine (25%) and PPX (5%), was similar to that found in adults, where 37% and 3% were excreted in the urine as 3-hydroxyropivacaine and PPX, respectively, with the remainder of the dose excreted as a number of quantitatively minor metabolites.9 In vitro, cytochrome isoenzyme subclass CYP1A2 is responsible for the metabolism of ropivacaine to 3-hydroxyropivacaine and cytochrome isoenzyme subclass CYP3A4 is responsible for the metabolism of ropivacaine to PPX,22 with CYP1A2 being the most important isozyme for the metabolism of ropivacaine in vivo.23 The activity of CYP1A2 reaches adult levels in children above the age of 7 yr24 and CYP3A4 reaches 3040% of adult activity as early as 1 month after birth.25 It is not surprising, therefore, that children above the age of 1 yr have a well developed capacity to eliminate ropivacaine.
Since neither the unbound volume of distribution nor the unbound clearance showed any apparent age-dependency when adjusted to bodyweight, dosing per kilogram of bodyweight is supported in this age group from a pharmacokinetic point of view.
There was no evidence of motor block in the lower limbs of any of the patients as they woke up. This finding is consistent with previous publications using ropivacaine 2 mg ml1 in children.3 4
As a result of the variation in the dermatomal level of the surgical intervention and the duration of the surgical procedure, it is difficult to assess postoperative analgesia adequately. Although analgesia was not a primary end-point and a simple pain-scoring system was used, postoperative analgesia was assessed as satisfactory in 90% of the patients during the study period.
The most common adverse events (vomiting, nausea and pruritus) may have been associated with the surgical procedure, the general anaesthetic and postoperative opioid treatment and are commonly seen during the postoperative period.
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Acknowledgements |
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Footnotes |
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References |
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2 Zaric D, Nydahl PA, Philipson L, Samuelsson L, Heierson A, Axelsson K. The effect of continuous lumbar epidural infusion of ropivacaine (0.1%, 0.2%, and 0.3%) and 0.25% bupivacaine on sensory and motor block in volunteers: a double-blind study. Reg Anesth 1996; 21: 1425[ISI][Medline]
3 Ivani G, Mereto N, Lampugnani E et al. Ropivacaine in paediatric surgery: preliminary results. Paediatr Anaesth 1998; 8: 1279[ISI][Medline]
4 Ivani G, Lampugnani E, Torre M et al. Comparison of ropivacaine with bupivacaine for paediatric caudal block. Br J Anaesth 1998; 81: 2478
5 Ivani G, Lampugnani E, De Negri P, Lönnqvist PA, Broadman L. Ropivacaine vs bupivacaine in major surgery in infants. Can J Anaesth 1999; 46: 4679[Abstract]
6 Engman M, Neidenström P, Norsten-Höög C, Wiklund S-J, Bondesson U, Arvidsson T. Determination of ropivacaine and [2H3]ropivacaine in biological samples by gas chromatography with nitrogenphosphorus detection or mass spectrometry. J Chromatogr B 1998; 709: 5767[ISI]
7 Arvidsson T, Eklund E. Determination of free concentration of ropivacaine and bupivacaine in blood plasma by ultrafiltration and coupled-column liquid chromatography. J Chromatogr B 1995; 668: 918[Medline]
8 Arvidsson T, Askemark Y, Halldin MM. Liquid chromatographic bioanalytical determination of ropivacaine, bupivacaine and major metabolites. Biomed Chromatogr 1999; 13: 28692[ISI][Medline]
9 Halldin MM, Bredberg E, Angelin B et al. Metabolism and excretion of ropivacaine in humans. Drug Metabol Disp 1996; 24: 9628
10 Lindahl SGE. In Sumner E, Hatch DJ, eds. Textbook of Paediatric Anaesthetic Practice. London: Baillière Tindall, 1989; 2
11 Rowland M, Tozer TN. Age and weight. Clin Pharmacokinet. Concepts and Applications, 3rd edn. Philadelphia, PA: Williams & Wilkins, 1995; 23045
12 Kokinsky E, Cassuto J, Sinclair R, Rubensson A, Nilsson K, Larsson LE. Topical wound anaesthesia in childrena temporary postoperative pain relief. Acta Anaesthesiol Scand 1999; 43: 2259[ISI][Medline]
13 Koinig H, Krenn CG, Glaser C et al. The doseresponse of caudal ropivacaine in children. Anesthesiology 1999; 90: 133944[ISI][Medline]
14 Da Conceicao MJ, Coelho L. Caudal anaesthesia with 0.375% ropivacaine or 0.375% bupivacaine in paediatric patients. Br J Anaesth 1998; 80: 5078[ISI][Medline]
15 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]
16 Katz JA, Bridenbaugh PO, Knarr DC, Helton SH, Denson DD. Pharmacodynamics and pharmacokinetics of epidural ropivacaine in humans. Anesth Analg 1990; 70: 1621[Abstract]
17 Jackson PR, Tucker GT, Woods HF, Phil D. Altered plasma drug binding in cancer: role of 1-acid glycoprotein and albumin. Clin Pharmacol Ther 1982; 32: 295302[ISI][Medline]
18 Lerman J, Strong HA, LeDez KM, Swartz J, Rieder MJ, Burrows FA. Effects of age on the serum concentration of 1-acid glycoprotein and the binding of lidocaine in pediatric patients. Clin Pharmacol Ther 1989; 46: 21925[ISI][Medline]
19 Erichsen C-J, 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]
20 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]
21 López Barrio AM, de Palma Gastón MA, Muñoz Conde J. Valoración del flujo sanguíneo portal, en niños sanos, mediante ecografía Doppler duplex. An Esp Pediatr 1996; 44: 459[Medline]
22 Ekström G, Gunnarsson U-B. Ropivacaine, a new amide-type local anaesthetic agent is metabolized by cytochromes P450 1A and 3A in human liver microsomes. Drug Metabol Disp 1996; 24: 95561
23 Arlander E, Ekström G, Alm C et al. Metabolism of ropivacaine in humans is mediated by CYP1A2 and to a minor extent by CYP3A4an interaction study with fluvoxamine and ketokonazole as in vivo inhibitors. Clin Pharmacol Ther 1998; 64: 48491[ISI][Medline]
24 Krul C, Hageman G. Analysis of urinary caffeine metabolites to assess biotransformation enzyme activities by reversed-phase high-performance liquid chromatography. J Chromatogr B 1998; 709: 2734[ISI]
25 Lacroix D, Sonnier M, Moncion A, Cheron G, Cresteil T. Expression of CYP3A in the human liver. Evidence that the shift between CYP3A7 and CYP3A4 occurs immediately after birth. Eur J Biochem 1997; 247: 62534[Abstract]