Pharmacokinetics and efficacy of ropivacaine for ... - Wiley Online Library

Pediatric Anesthesia 2005

15: 739–749

doi:10.1111/j.1460-9592.2004.01550.x

Pharmacokinetics and efficacy of ropivacaine for continuous epidural infusion in neonates and infants ¨ S EN B ER G M B C h B F F A * †, JE N N Y T H O M A S ADRIAN T. BO M B C h B F F A †, L A R I S S A C R O N J E M B C h B F C A †, T E S S A L O P EZ M B B S F R C A ( E N G ) †, P E T ER M . C R E A N M B B C h F F A R C S I ‡, U R B A N GU S T A FS S O N P h D § , G U N I L LA H U L E D A L M S c P H A R M § A N D LARS E. LARSSON MD PhD§ *Department Anaesthesia, Faculty Health Sciences, University Natal, Durban, South Africa, †Department Anaesthesia, Red Cross Children’s Hospital, University Cape Town, Cape Town, South Africa, ‡Royal Belfast Hospital for Sick Children, Belfast, UK and §AstraZeneca R&D, So¨derta¨lje, Sweden

Summary Introduction: The primary objective of this noncomparative study was to evaluate the pharmacokinetics of ropivacaine during a 48–72-h continuous epidural infusion of ropivacaine in children under 1 year. The secondary objectives were to assess efficacy and safety. Methods: Neonates and infants (ASA I–III, gestational age ‡37 weeks, ‡2.5 kg, scheduled for major abdominal or thoracic surgery) were included and separated into age groups: 0–30 (neonate), 31–90, 91–180, and 181–365 days. Ethics committee approval and informed parental consent were obtained before inclusion. An epidural catheter was introduced under general anesthesia at the appropriate dermatomal level. An initial bolus dose (0.9–2.0 mgÆkg)1 of ropivacaine 0.2%) was followed by an epidural infusion (0.2 mgÆkg)1Æh)1 for infants 180 days). Plasma samples were collected every 12 h from 24 h, and on termination of the epidural infusion. Postoperative pain was evaluated using both the Objective Pain Scale and a four-graded descriptive scale. Results: Forty-five infants, median age 116 (0–362) days, were included. Forty-three and 19 patients received an infusion for at least 48 and 72 h, respectively. Satisfactory analgesia was provided in the majority, only 20 patients were given supplementary medication during the infusion. In all age groups, plasma concentrations of unbound ropivacaine leveled at 24 h, without any further increase at 48 and 72 h. Because of lower clearance of unbound ropivacaine in neonates (mean 33 mlÆmin)1Ækg)1) than in infants above the age of 30 days (80, 124, and 163 mlÆmin)1Ækg)1, respectively, in the age groups 31–90, 91–180, and 180–365 days), unbound ropivacaine concentrations at the end of infusion were higher in neonates [median

Correspondence to: Adrian T. Bo¨senberg, Department Anaesthesia, Faculty of Health Sciences, University Cape Town, Anzio Road, Observatory, 7925, Cape Town, South Africa (email: [email protected]). 2005 Blackwell Publishing Ltd

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¨ S E N B E R G ET AL . A.T. BO

0.10 mgÆl)1 (0.04–0.21 mgÆl)1)] than in infants >30 days [median 0.03 mgÆl)1 (0.003–0.10 mgÆl)1)]. Conclusion: Epidural infusions (0.2–0.4 mgÆkg)1Æh)1 ropivacaine) provided satisfactory pain relief in neonates and infants under 1 year. As plasma concentrations of unbound ropivacaine were not influenced by the duration of the infusion, ropivacaine can be safely used for postoperative epidural infusion for 48–72 h. Levels of unbound ropivacaine were higher in the neonates than in the infants, but were below threshold concentrations for CNS toxicity in adults (‡0.35 mgÆl)1). This should not preclude the use of ropivacaine infusions in neonates but suggests a need for caution during the first weeks of life. Keywords: local anesthesia; neonate; infant; ropivacaine; epidural infusion

Introduction Epidural analgesia in combination with light general anesthesia is a useful alternative for infants and neonates undergoing major surgery (1,2). Apart from providing good intraoperative and postoperative analgesia, epidural blockade has beneficial effects on the humoral, metabolic, and hemo dynamic responses to surgery (3). Ropivacaine, a long-acting, single enantiomer, amide local anesthetic (4), has a number of advantages that could be considered important in infants. These include lower cardiotoxicity (5,6) than equal concentrations of racemic bupivacaine and a higher threshold for CNS toxicity of the unbound concentration (7). The greater degree of block in nerve fibers of pain transmission than of motor function for a given concentration (4) would be of further benefit. Recent studies have documented the use of single dose caudal ropivacaine in neonates (8,9) and by continuous infusion in children between 0.3 and 7.3 years (10) but to date there are no studies describing continuous epidural infusions in neonates and younger infants. There is limited information with regard to the safety of continuous local anesthetic infusions in infants under 1 year. Some authors have raised concerns about the safety of epidural infusions in this age group because of the elevated plasma concentrations of bupivacaine, particularly after 48 h, during prolonged infusions (11–13). However, these studies are based on total plasma concentrations

of bupivacaine only (with increased concentrations because of a stress-induced increase in the binding protein, a1-acid glycoprotein, AAG) or a limited duration of the continuous epidural infusion without reaching steady-state. Plasma concentrations of unbound ropivacaine are expected to level off during an epidural infusion, as ropivacaine is eliminated by liver metabolism with an intermediate to low hepatic extraction ratio in adults (14) as well as in children (15). Consequently, plasma concentration of unbound ropivacaine at steady-state will depend on clearance of unbound ropivacaine. In a previous study with a single caudal block of ropivacaine (2 mgÆkg)1) clearance of unbound ropivacaine was lower in neonates (mean 58 mlÆmin)1Ækg)1) than in infants (mean 180 mlÆmin)1Ækg)1) because of a lower metabolic capacity (9). The aim of this study was to evaluate both the pharmacokinetics and the efficacy and safety of ropivacaine during a continuous epidural infusion in neonates and infants under 1 year. Pharmacokinetic data are crucial before any dosage recommendations for continuous epidural infusion can be made. In such an analysis, unbound concentration measurements are especially important as they are the primary determinants of toxicity. An epidural bolus dose of 2 mgÆkg)1 was considered appropriate from a safety point of view based on previous pharmacokinetic data, whereas different infusion rates were chosen for infants below 180 days (0.2 mgÆkg)1Æh)1) and above 180 days (0.4 mgÆkg)1Æh)1) because of the 2005 Blackwell Publishing Ltd, Pediatric Anesthesia, 15, 739–749

E P I D U R A L R O P I V A C A I N E IN F U S I O N IN N E O N A T E S A N D IN FA N T S

age-related variations in unbound clearance during the first year of life (9).

Material and methods Patients The study was performed in three centers, two in South Africa (King Edward VIII Hospital, Durban, South Africa and Red Cross Children’s Hospital, Cape Town, South Africa) and one in the UK (Royal Belfast Hospital for Sick Children). Term neonates and infants, ASA I–III, weighing ‡2.5 kg, scheduled for major abdominal or thoracic surgery were included. In order to have an even age distribution, these were stratified into groups according to age, i.e. 0–30 (neonate), 31–90, 91–180, and 181–365 days. The study protocol was approved by the Ethics Committee at all three centers and written informed parental consent was obtained prior to inclusion in the study. The consent form and written explanation of the procedure was translated into the first language of the parents and the protocol was explained in their language of choice (Afrikaans, English, Xhosa, or Zulu). The Medical Authorities in both South Africa and the UK approved the study.

Anesthetic procedure No premedication was given and general anesthesia was standardized to an inhalational induction with halothane or sevoflurane, tracheal intubation with or without muscle relaxants and intermittent positive pressure ventilation. No opioids were administered unless the epidural failed or was considered inadequate. An epidural catheter was introduced under general anesthesia prior to the start of surgery. Caudal, sacral, lumbar, and thoracic epidural techniques were all considered acceptable for the purposes of the study and were performed at the discretion of the anesthesiologist concerned. Once stable under anesthesia the patient was turned to a lateral decubitus position with legs flexed. An epidural catheter of appropriate size (19G Tuohy Portex; Hythe, Kent, UK) was introduced at the dermatomal level appropriate for the planned surgery or gently advanced from the sacral hiatus to the desired level. After a negative aspiration for 2005 Blackwell Publishing Ltd, Pediatric Anesthesia, 15, 739–749

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blood or cerebrospinal fluid, an initial bolus dose (0.5–1 mlÆkg)1 ropivacaine 0.2%) was given. The epidural infusion (0.2 mgÆkg)1Æh)1 for infants 180 days) was started immediately after the epidural catheter had been secured. Postoperative pain was evaluated by a study nurse or the investigators using both a four-graded descriptive scale (no, mild, moderate, or severe pain) and the Objective Pain Scale (OPS) (16). The OPS equates pain and discomfort with crying, movement, agitation, body language, and changes in systolic blood pressure. Each parameter scored 0–2; and a total score ranging from 0–10 was recorded. An OPS score >3 or moderate or severe pain required administration of supplementary analgesia or adjustment of the epidural infusion rate if the level of blockade was considered inadequate. The pain assessments were performed every 2 h for the first 8 h after the initial ropivacaine bolus and thereafter at 0600, 1200, and 1800 h daily while the infusion was in progress. In every patient the result of the four-graded scale was recorded before the evaluation of the OPS score. Motor block was assessed at the same time as the evaluation of pain and was simply defined as being present or absent. Evidence of spontaneous movement or movement in response to stimulation of the hips, knees, and ankles was recorded in both legs. An electrocardiograph (ECG) was recorded daily and on termination of the epidural infusion in order to detect any changes in the ECG variables and if detected, to subsequently determine whether these changes could be correlated with plasma concentrations of ropivacaine and/or its metabolites.

Blood and urine sampling Venous blood samples for determination of total and unbound ropivacaine, total and unbound 2,6-pipecoloxylidide (PPX), the major metabolite, and AAG were collected prior to placement of the epidural (baseline sample) and 12 hourly from the start of the epidural infusion. Only total ropivacaine was determined in the initial 12-h sample. A final sample was taken on termination of the epidural infusion. These samples were placed in heparinized tubes (Venoject; Terumo, Leuven, Belgium), and plasma was

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separated by centrifuge at room temperature within 30 min of collection. The plasma was stored in polypropylene tubes (Cryotube; A/S Nunc, Ros Kilde, Denmark) at )20C until assayed. In 39 patients where a urinary catheter was placed as part of their perioperative management, urine was collected to determine the concentrations of ropivacaine and its metabolites 3-hydroxy-ropivacaine (3-OH-R) and PPX. The volume of urine produced every 12 h was recorded and two representative 5 ml samples were taken from each 12-h collection and stored in polypropylene tubes (Cryotube; A/S Nunc) at )20C or below until assayed. Frozen samples were kept on dry ice during transportation to So¨derta¨lje (Sweden) where they were assayed in the AstraZeneca R&D laboratories. Analysts were unaware of the age of the infants from whom the samples were taken.

Bioanalytical methods The total concentration of ropivacaine in plasma was determined by gas chromatography with a nitrogen sensitive detector with pretreatment based on liquid–liquid extraction (17). The limit of quantification (LOQ) was 0.0027 mgÆl)1 as base and the interassay coefficient of variation (CV) was 6.8% (n ¼ 10, sample volume 100 ll). The total concentration of PPX in plasma was determined by coupled column liquid chromatography with mass spectrometric detection with electrospray ionization with pretreatment based on acidification and ultrafiltration. LOQ was 0.0023 mgÆl)1 as base and the inter-assay CV was 4.3% (n ¼ 10) using 0.5 ml samples. Unbound ropivacaine and PPX in plasma were determined by coupled column liquid chromatography with mass spectrometric detection using electrospray ionization with pretreatment based on ultrafiltration of plasma pH adjusted to 7.4 at 37C. LOQ was 0.0027 mgÆl)1 for ropivacaine (inter-assay CV 4.8%, n ¼ 6) and 0.0023 mgÆl)1 for PPX (interassay CV 4.5%, n ¼ 6) using 0.5 ml of plasma. a1-Acid glycoprotein was determined by an immunoturbidometric method. LOQ was 3.0 lmolÆl)1 and the CV was 2.1% at 20.7 lmolÆl)1 using 60 ll of plasma. The concentration of ropivacaine, 3-OH-R and PPX in the urine was determined using coupled

column liquid chromatography with gradient elution and electrospray tandem mass spectrometry. The sum of the conjugated and unconjugated concentration of 3-OH-R was determined by acid hydrolysis using a urine volume of 1.0 ml. The LOQ was 0.3, 1.7, and 0.8 lmolÆl)1 for ropivacaine, 3-OH-R, and PPX, respectively. The mean range of accuracy varied between 97 and 103% of a nominal value of each and the precision given as the coefficients of variation ranged between 3.4 and 8.7%.

Pharmacokinetic calculations The unbound fraction (fu) of ropivacaine and PPX was calculated as unbound concentration divided by total concentration in the same sample. Apparent unbound clearance of ropivacaine at steady-state (CLu,app,ss) was calculated as the rate of epidural infusion/the steady-state concentration of unbound ropivacaine (Cuss). Cuss was calculated as the mean of three (n ¼ 20) or four (n ¼ 20) plasma concentrations of unbound ropivacaine during the epidural infusion. The central nervous toxicity of unbound PPX, in rats, is about one-twelfth of that of unbound ropivacaine (Magnus M. Halldin, AstraZeneca R&D, Oral and AstraZeneca internal written communication). In order to estimate the additive CNS activity the sum of unbound ropivacaine and that of onetwelfth of unbound PPX were added together (based on concentrations expressed as mgÆl)1) in samples where both unbound ropivacaine and PPX were determined. In the majority of patients urine collection was terminated during or shortly after completion of the epidural infusion. However, in 14 patients, where urine was collected for at least 10 h after the end of the epidural infusion, the molar fraction of the administered dose excreted in urine as ropivacaine, 3-OH-R and PPX was calculated as well as the relative fraction of the recovered amount in urine consisting of ropivacaine, 3-OH-R, and PPX. In some patients, from whom urine was collected for at least 20 h after the end of the epidural infusion, the half-life of ropivacaine, 3-OH-R and PPX could be calculated by linear regression of the linear and declining part of the log-linear plot of the excretion rate versus time curve after the end of 2005 Blackwell Publishing Ltd, Pediatric Anesthesia, 15, 739–749


infusion. WinNonlinTM software (Pharsight Corporation, PaloAlto, CA, USA) was used for these calculations.

Statistics A two-sided t-test was used to compare mean values. Pearson correlation coefficient was used to investigate the relation between different variables. Chi-squared test was used to compare fractions. Statistical significance was assumed for P < 0.05.

Results Patients Forty-five infants were included in the study. The age range was between 0 and 362 days and the weight range was between 2.6 and 10.9 kg. There was an equal gender distribution – 22 boys and 23 girls (Table 1). The majority of the patients had ASA classification II. The ASA III classification was used for eight patients and included infants with necrotizing enterocolitis, patent ductus arteriosus, biliary atresia, tracheoesophageal fistula, and double-outlet right ventricle. All 11 neonates had surgery during the first week of life. The surgical procedures are shown in Table 2. The median duration of surgery was 1.3 h (range 0.5–3.3 h). The median time to discharge from hospital was 6 days for the total population (range 2–45 days) and 11 days for the neonates. All patients had general anesthesia before the introduction of the epidural catheter. Most patients received halothane in oxygen/nitrous oxide combined with muscle relaxants after an initial sevo-

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flurane induction. All patients received intravenous fluids comprising lactated Ringers solution. Blood loss was estimated to be 0.05). The highest value was seen in the patient where the catheter was dislodged after 8 h. Only 9% of the patients were at one or several occasions judged to have moderate or severe pain when using the four-graded descriptive scale. Moderate or severe pain was noted simultaneous to eight of nine observations with OPS scores between 6 and 10, and with one of 20 observations with OPS scores between 4 and 5. None of the infants had evidence of motor block when assessed at the times stipulated in the protocol. There were no significant complications related to the epidural. The most common adverse events reported were early postoperative fever (24%), infiltration at the intravenous infusion site (22%) and vomiting (11%). No clinically significant changes in systolic and diastolic blood pressure, peripheral oxygen saturation, or body temperature were recorded. However T-wave changes (11%) and relative tachycardia (9%) were noted on the daily ECG. In the infants with T-wave changes plasma concentrations of unbound ropivacaine were between 0.03 and 0.10 mgÆl)1. All patients had higher concentrations at other time points during the epidural infusion. Four patients were reported to have had serious adverse events, namely bronchospasm, abdominal distention, infection (0–30 days age group), and oliguria (31–90 days age group). None were considered to be related to study drug or epidural, and all patients recovered.

31–90 days (n ¼ 10)

9 6 6 4 4 4 2 2 2 3 3

0–30 days (n ¼ 11)

Colostomy Urological surgery Anorectal surgery Bile duct anastomosis (Kasai) Ligation patent ductus arteriosus Fundoplication (Nissen) Closure colostomy Closure exomphalus Necrotizing enterocolitis, ileostomy Other abdominal surgery Other thorax surgery

Age group

Table 2 Surgical procedures

181–365 days [n ¼ 14 (24 h); n ¼ 13 (48 h)]


Table 3 Pharmacokinetic parameters of ropivacaine, PPX, and AAG during a 48–72-h epidural infusion of ropivacaine started immediately after an epidural bolus of 0.9–2 mgÆkg)1 using ropivacaine 0.2%. Values are given as mean ± SD (min–max)

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Pharmacokinetics Plasma Baseline AAG concentrations were slightly lower in the neonates than in the older patients but there was no significant correlation between baseline concentrations and age (P > 0.05). In five patients in the 0–30-day age group AAG concentrations were below 10 lmolÆl)1, whereas none of the other patients had baseline values below 10 lmolÆl)1. AAG plasma concentrations increased postoperatively in all age groups (P < 0.01) (Table 3). The highest AAG plasma concentrations, both initially and at end of infusion, were observed in a 3-day-old neonate with necrotizing enterocolitis that required an ileal resection (48 and 56 lmolÆl)1) and a 56-day-old infant with Hirschsprung’s disease that required a colostomy (45 and 68 lmolÆl)1). Plasma concentrations of total ropivacaine were similar at 24 and 48 h in all age groups and there was no increase in total ropivacaine after 48 h in any of the age groups (Table 3). The highest individual plasma concentration of ropivacaine (total 9.2, unbound 0.22 mgÆl)1) was determined at 24 h in the neonate with necrotizing enterocolitis (high AAG concentrations) and the second highest individual ropivacaine concentration (total 5.8, unbound 0.06 mgÆl)1) was determined at 24 h in the infant with Hirschprung’s disease. CLu,app,ss in these two neonates was 26 and 72 mlÆmin)1Ækg)1, respectively. Ropivacaine concentrations were unexpectedly low (total concentration 0.05). In the remaining 14 patients with values from all time points there were no significant differences from 24 to 48 h but a significant decrease was observed from 48 to 72 h (P < 0.001, mean values 0.05 and 0.03 mgÆl)1). The unbound fraction of ropivacaine ranged between 1 and 12% without any apparent change 2005 Blackwell Publishing Ltd, Pediatric Anesthesia, 15, 739–749

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over time or between age groups. The lowest unbound fractions of ropivacaine were observed in patients with high AAG concentrations. CLu,app,ss, calculated in all patients except two with the low ropivacaine concentrations, increased significantly with age (Table 3, Figure 2, r2 ¼ 0.67, P < 0.001). Mean clearance in neonates was 33 mlÆmin)1Ækg)1 (2.0 lÆh)1Ækg)1) in comparison with 163 mlÆmin)1Ækg)1 (9.8 lÆh)1Ækg)1) in infants above 180 days. Consequently, plasma concentrations of unbound ropivacaine were higher in neonates than in the older age groups (significant differences at 24, 48, and 72 h, P < 0.01 and 0.001) with the same infusion rate. Plasma concentrations of unbound ropivacaine did not differ between children aged 30– 180 days and children above 180 days of age, despite a higher infusion rate of ropivacaine in children older than 180 days. Unbound ropivacaine concentrations at the end of infusion (Figure 3) were significantly higher in neonates [mean 0.11 mgÆl)1 (0.04–0.21 mgÆl)1)] than in infants >30 days [mean 0.03 mgÆl)1 (0.003–0.10 mgÆl)1)]. Plasma concentrations of PPX were measured at 48 and 72 h. The unbound PPX concentrations were not significantly different from 48 to 72 h (P > 0.05) nor were there significant differences in the concentrations observed among the four age groups (Table 3). Plasma concentrations of total PPX also did not show any statistically significant differences over the same time intervals during the continuous infusion. The unbound fraction of PPX ranged between 15 and 88% without any apparent difference during the epidural infusion or between age groups. The ratio between unbound PPX and unbound ropivacaine ranged between 1 and 11% at 24 h, and between 1 and 21% at 72 h. There were no significance correlation between this ratio and age (P > 0.05). The sum of unbound ropivacaine and unbound PPX/12 was higher in the neonates than in the older infants mainly because of higher concentrations of unbound ropivacaine. The highest individual value of this sum was 0.24 mgÆl)1 in a 2-day-old neonate. Urine The urinary recovery of ropivacaine, 3-OH-R, and PPX added together, ranged between 7 and 41% of the administered dose with mean recovery values of 9, 11, 18, and 30% in the 0–31, 31–90, 91–180, and

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Figure 1 Individual plasma concentrations of total and unbound ropivacaine in the four age groups (0–30, 31–90, 91–180, and 181–365 days) during a 48–72-h epidural infusion of ropivacaine started immediately after an epidural bolus of 0.9–2 mgÆkg)1 using ropivacaine 0.2% (0.2 mgÆkg)1Æh)1 for infants £180 days; and 0.4 mgÆkg)1Æh)1 for infants >180 days).

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Figure 2 Ropivacaine clearance (CLu,app,ss) in relation to age (r2 ¼ 0.67, P < 0.001).

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Figure 4 Fraction of ropivacaine metabolites recovered in urine as ropivacaine, PPX, and 3-OH-R (%). Patients with urine collected during the epidural infusion and for at least 10 h after the completion of the epidural infusion are included. Results are given as mean values. 3-OH-R: P < 0.01 for age groups 0–30 days vs. 181– 365 days. Ropivacaine: P < 0.001 for age groups 0–30 days vs. 181–365 days.

corresponding figure in the oldest age group was 7% (Figure 4). The terminal half-life for ropivacaine, calculated in five patients on three to six data points was 10 h (2 days old), 6 and 7 h (3 days old), 12 h (67 days old), and 5 h (261 days old). Figure 3 Plasma concentrations of unbound ropivacaine at the end of a 48– 72-h epidural infusion of ropivacaine started immediately after an epidural bolus of 0.9–2 mgÆkg)1 using ropivacaine 0.2% (0.2 mgÆ kg)1Æh)1 for infants £180 days; and 0.4 mgÆkg)1Æh)1 for infants >180 days).

181–365-day age groups, respectively, in patients with urine collected for at least 10 h after the end of the epidural infusion. In all age groups the most abundant urinary metabolite was PPX with approximately 70% of the recovered amount in urine being PPX (Figure 4). The terminal half-life of PPX, based on five or six data points, was 10 h (61 days old), 5 h (107 days old), and 8 h (261 days old). In 0–30-day-old neonates, only 4% of the recovered amount in urine consisted of 3-OH-R (the most abundant metabolite in adults), whereas 24% of the recovered amount consisted of 3-OH-R in 180–365-day-old infants (Figure 4). The terminal half-life of 3-OH-R calculated in two patients in the oldest age group was approximately 4 h. In neonates 24% of the recovered amount in urine was excreted as unchanged ropivacaine, whereas the 2005 Blackwell Publishing Ltd, Pediatric Anesthesia, 15, 739–749

Discussion This is the first study to examine parent (bound and unbound) and metabolite concentrations of ropivacaine in neonates following epidural infusions for 48–72 h. We report lower clearance of unbound ropivacaine by neonates (mean 33 mlÆmin)1Ækg)1) compared with infants over 180 days (mean 163 mlÆmin)1Ækg)1). These results are similar to those found after a single shot caudal block with ropivacaine 0.2% (mean unbound clearance 58 and 180 mlÆmin)1Ækg)1 in 30- and 270-day-old patients, respectively) (9) and to those values obtained during a continuous epidural infusion of 0.4 mgÆkg)1Æh)1 ropivacaine in 0.3–7.3-year-old patients (mean 220 mlÆmin)1Ækg)1) (10). Unbound clearance in the oldest age group in our study was also similar to those recorded after a single shot caudal block in 1–9-year-old patients (mean 151 mlÆmin)1Ækg)1) (15). As a consequence of these age-related clearance variations the unbound ropivacaine plasma concentrations were higher in neonates (max: 0.22 mgÆl)1) than in the older age groups (max: 0.13 mgÆl)1).

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Furthermore our results show that plasma concentration of unbound ropivacaine levels off after 24 h infusion for all age groups including neonates. This is important and implies that long-term epidural infusions of ropivacaine may be administered to both infants and neonates. a1-Acid glycoprotein is responsible for binding basic drugs such as ropivacaine, which are highly protein bound. In this study the AAG concentrations were slightly lower in the neonates compared with the other groups, which is in accordance with previous studies (18). AAG is an acute phase protein and may be elevated by surgical stress particularly in infants with infections or undergoing emergency surgery (18). The AAG concentrations increased postoperatively in all age groups, which contributed to elevated plasma concentrations of total ropivacaine. PPX is an active metabolite of ropivacaine, with one-twelfth of the toxicity of ropivacaine. The maximum individual value of plasma concentrations of unbound ropivacaine and one-twelfth of unbound PPX was 0.24 mgÆl)1 in neonates below the age of 30 days and 0.16 mgÆl)1 in infants above the age of 30 days, which is below the threshold concentrations for CNS toxicity in adults (0.35 mgÆl)1) (7). The presence of PPX in plasma in all age groups studied is supported by the urinary results, where PPX is recovered in the same relative amounts in the neonates as in the older infants. This suggests that CYP3A7 (the fetal form of CYP3A4) (19), with peak liver levels 1 week postpartum (20), is capable of metabolizing ropivacaine to PPX in the early postpartum period. In adults, CYP3A4 is responsible for the demethylation of ropivacaine to PPX. In the present study, urinary excretion of 3-OH-R, which is formed by oxidation of ropivacaine by CYP1A2, was of minor importance in neonates, but increased above the age of 90 days. This is in accordance with the development of CYP1A2, which does not reach full activity until the end of the first year (21). Pain assessment is necessary for individualized titration of analgesics and evaluation of treatment. In this uncontrolled study