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Anesth Analg 2001;93:893-897
© 2001 International Anesthesia Research Society

PEDIATRIC ANESTHESIA

The Pharmacokinetics of Epidural Ropivacaine in Infants and Young Children

Mary Ellen McCann, MD*, Navil F. Sethna, MD ChB*, Jean-Xavier Mazoit, MD PhD{dagger}, Masayuki Sakamoto, BS{ddagger}, Nader Rifai, PhD{ddagger}, Todd Hope, BA{ddagger}, Lorna Sullivan, RN*, Susan G. Auble, BSN JD*, and Charles B. Berde, MD PhD*

Departments of *Anesthesia and {ddagger}Laboratory Science, Children’s Hospital and Harvard Medical School, Boston, Massachusetts; and {dagger}Laboratoire d’Anesthesie Universite Paris-Sud, Le Kremlin-Bicetre, France

Address correspondences and reprint requests to Mary Ellen McCann, MD, Department of Anesthesia, Children’s Hospital, 300 Longwood Ave., Boston, MA 02115. Address e-mail to McCann_M{at}tch.harvard.edu


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
The pharmacokinetic variables of ropivacaine were characterized after epidural bolus injection in pediatric patients. The subjects, 7 infants (aged 3–11 mo) and 11 young children (aged 12–48 mo), received 1.7 mg/kg of ropivacaine via a lumbar epidural catheter. Total plasma concentrations of ropivacaine measured over 24 h were assayed by high-pressure liquid chromatography, and pharmacokinetic modeling was performed by Nonlinear Mixed Effects Modeling analysis. The median peak venous plasma concentrations (Cmax) in infants and young children were 610 µg/L (interquartile range [IQR], 550–725 µg/L) and 640 µg/L (IQR, 540–750 µg/L), respectively. The median times to maximum plasma ropivacaine concentration (Tmax) were 60 min (IQR, 60–120 min) in infants and 60 min (IQR, 30–90 min) in young children. There were no statistical differences between median values of Cmax and Tmax between infants and young children. The calculated clearance (CL) in infants was 4.26 mL · min-1 · kg-1 (9% coefficient of variation), and in young children it was 6.15 mL · min-1 · kg-1 (11% coefficient of variation). The CL for infants was significantly less than the CL for young children (P < 0.01). The volume of distribution was estimated to be 2370 mL/kg (9% coefficient of variation) for both young children and infants. No systemic toxicity was observed in either group.

IMPLICATIONS: This study revealed that the pharmacokinetic variables of lumbar epidural bolus ropivacaine in pediatric patients aged 3 to 48 mo are similar to those of adults, except that drug clearance was less in infants compared with older children.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Ropivacaine is a long-acting amide local anesthetic developed to be a safer and perhaps more sensory-selective alternative to bupivacaine (1,2). In volunteer studies in adults, ropivacaine exhibited less central nervous system and cardiac toxicity than bupivacaine, with adults tolerating an average of 25% more ropivacaine infused IV than bupivacaine before the onset of signs of central nervous system toxicity (3). Ropivacaine may also have the further advantage of causing a less extensive motor block of shorter duration while inducing a sensory block of similar quality to bupivacaine when administered in equal doses to children for caudal blocks (4,5). These properties suggest that ropivacaine may be particularly suited for pediatric postoperative epidural infusions.

Given the potential benefits of less systemic toxicity and motor blockade, we studied the pharmacokinetic variables of a single bolus dose of lumbar epidural ropivacaine in infants and young children.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
After obtaining approval from the Committee on Clinical Investigations and written informed consent from the parents, we studied 7 infants (3–11 mo) and 11 young children (12–48 mo) who were undergoing lower abdominal, pelvic, or lower extremity procedures. All participants were ASA physical status I or II.

General anesthesia was induced with either sevoflurane in 60% nitrous oxide and 40% oxygen briefly or IV sodium thiopental 4–8 mg/kg, and it was maintained with isoflurane (end-tidal concentrations up to 1.5%) in oxygen 30% and air. Muscle relaxation was accomplished with pancuronium, the trachea was intubated, and ventilation was controlled to maintain the end-tidal CO2 between 35 and 40 mm Hg. Patients were then placed in a lateral decubitus position, and 20-gauge polyamide catheters were placed for lumbar epidural anesthesia by using a loss of resistance to saline technique. After a test dose of lidocaine 1.5% with epinephrine 5 µg/mL, ropivacaine 0.2%, 0.85 mL/kg (1.7 mg/kg), for infants and young children was injected over 4 min via the lumbar epidural catheter. An epidural infusion of bupivacaine 0.1% with fentanyl 2 µg/mL solution was started 30 min after the ropivacaine epidural bolus at a rate of 0.3 mL · kg-1 · h-1. A peripheral IV catheter (22- or 20-gauge) was placed for maintenance fluids, and a separate peripheral IV catheter was placed in a different limb for venous blood sampling.

One milliliter of peripheral venous blood was obtained immediately before epidural injection of ropivacaine (control) and at 10, 20, 30, 60, and 90 min and 2, 8, and 24 h for all subjects after the start of the epidural bolus. Blood was collected in heparin anticoagulated glass tubes, and the plasma was immediately separated by centrifugation and stored at -18°C until assayed.

The assay of the plasma concentration of ropivacaine was performed by high-pressure liquid chromatography with an ultraviolet-sensitive detector and a simple solid phase extraction (6). In brief, plasma samples, standards, and controls containing the internal standard pentycaine were added to the preconditioned extraction columns (Clean Screen; United Chemical, Bristol, PA). Drugs of interest were then eluted with a methanol/ammonium solution. Eluents were dried and reconstituted with the mobile phase (acetonitrile, methanol, and phosphate buffer), and 50 µL was injected into the high-pressure liquid chromatograph (LC-10A Liquid Chromatograph; Shimadzu Scientific Instrument, Columbia, MD) (LC-8DB column; 5-µm particles size, 5 x 4.6 mm, Supelco, Bellefonte, PA). The signal was monitored at 210 nm. The retention time for ropivacaine was 1.9 min. The assay possessed linearity up to 2000 µg/L and sensitivity to at least 10 µg/L. The average recovery was 98%, and run-to-run reproducibility was <8.5% for ropivacaine at a wide range of concentrations. Determinations were precise and accurate at plasma concentrations >10 µg/L. Control experiments were performed in our clinical laboratory with plasma samples containing lidocaine, bupivacaine, or fentanyl to confirm that these drugs do not interfere with measurements of ropivacaine by this technique. Peak ropivacaine concentration (Cmax) and the time to reach the peak (Tmax) were recorded for each patient and are reported as the median value and interquartile range.

We used a population approach for parametric analysis by using Nonlinear Mixed Effects Modeling (NONMEM) (version V, level 1; NONMEM Project Group, University of California at San Francisco, CA). This nonlinear regression program is designed to fit general statistical models for repeated measures with special focus on population pharmacokinetics. It increases the power of the statistical analysis by using a global fitting approach rather than the usual two-stage approach. Linear pharmacokinetics with first-order absorption and elimination were considered. The choice between a one- or a two-compartment model was made with the Akaike criterion (7). A full model with different structural variables for clearance (CL), volume of distribution (V), and absorption rate constant (Ka) for each age group was first built. We did not correct CL and V for bioavailability because ropivacaine absorption from the epidural space is complete (8,9). The full model considered infants and young children as two samples drawn from two different populations and having separate variables for CL, V, and Ka. Pharmacokinetic variables were calculated with the following equation:

equation


where {theta} is the individual variable, TV{theta} is the typical value of the variable, and {eta}{theta} is the associated intersubject variability variable with mean 0 and variance {omega}2 (a common {eta}{theta} was considered for both populations). A constant coefficient of variation was used to model intrasubject variability, i.e., the residual differences between observed and predicted concentrations. The usual first-order method was used. Reduced models were successively tested. These models considered common Ka, CL, and V or CL and V for the two populations (infants and young children). The choice between the full model and the reduced models was made with the likelihood ratio test (10). The aim was to find a reduced model in which the difference in objective function (Table 1) was not statistically different from the full model, so no important variable has been removed from the model. Estimated variables are reported as typical population value (coefficient of variation of estimate), and 95% confidence intervals were calculated with the interindividual variability variable {omega}2.


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  		Table 1.  Model Building and Statistical Significancea
 
Cmax and Tmax were compared between groups by use of the Mann-Whitney U-test, with P < 0.05 considered significant. CL and V were compared by using the likelihood ratio test, with a difference in the objective function of 6.635 ({chi}2 with 1 df, P = 0.01) considered significant.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
There was no evidence of systemic local anesthetic toxicity in any patient. Seven infants were ages 3 to 11 mo (6.6 ± 2.8 mo) (mean ± SD), and 11 young children were ages 12 to 48 mo (34.7 ± 12.4 mo). In the Young Children and Infant groups, two children had no sampling at 60 min, and one child and two infants had no sampling at 24 h after injection.

The mean weight of patients in this study was 8.2 ± 1.6 kg in the Infant group and 13.3 ± 2.4 kg in the Young Children group. The mean duration of surgery was 4.0 ± 1.7 h in the Infant group and 4.6 ± 1.2 h in the Young Children group.

Table 2 summarizes the descriptive data. The median values of the Cmax were 610 µg/L (interquartile range [IQR], 550–725 µg/L) in Infants and 640 µg/L (IQR, 540–750 µg/L) in Young Children. The Cmax measured was 1055 and 1015 µg/L in the Infants and Young Children, respectively. The median Tmax was 60 min (IQR, 60–120 min) for Infants and 60 min (IQR, 30–90 min) for Young Children. There were no statistically significant differences between median values of Cmax and Tmax values between the two groups.


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  		Table 2.  Peak Concentration (Cmax) and Time to Peak (Tmax) in the Two Groups
 
The data were best fitted with a one-compartment model (Fig. 1). The best model that fit the data considered similar absorption from the epidural space in both groups and similar V (on a weight basis) for Infants and Young Children. This Reduced Model 1 with common Ka and V was not statistically different from the full model with all variables relevant for all groups, whereas Reduced Models 2 and 3, which considered common CL for all groups, were statistically different from the full model (Table 1). CL in the Infant group was significantly less than that in the Young Children group (Table 3). Plasma ropivacaine concentration-time data are shown in Figure 2.



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  		Figure 1. Adequacy of fitting. Predicted versus observed ropivacaine concentration. Data are represented on a Cartesian plot (left) and on a log-log plot (right).

 

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  		Table 3.  Pharmacokinetic Variables Obtained with Model 1 (Table 2)
 


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  		Figure 2. Concentration time data in the two groups; data are measured values (light lines) and estimated population values (thick line).

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
Lumbar epidural ropivacaine in a dose of 1.7 mg/kg gives safe plasma concentrations in infants and young children. The median Cmax values varied from 610 µg/L in young children to 640 µg/L in infants. The highest peak individual plasma concentration (1055 µg/L) was below the reported maximum tolerated venous plasma concentration of 2100 µg/L in adult volunteers (3).

Our study revealed that Tmax occurred around 60 minutes in both groups. Our finding of a relatively prolonged Tmax is in agreement with previous studies of ropivacaine in caudal blockade in anesthetized children (11–14). Direct comparison of Tmax between ropivacaine and bupivacaine in anesthetized children showed a longer Tmax for ropivacaine compared with bupivacaine (14). The Tmax for bupivacaine in the study of Ala-Kokko et al. (14) was similar to those in other previous studies of epidural bupivacaine in anesthetized children (15,16). In contrast, most studies of epidural ropivacaine in awake adults gave shorter mean Tmax values, namely, 20, 24, and 25 minutes (9,17,18). In one study, however, Katz et al. (19) did find a relatively prolonged Tmax (1.6 hours) in one subgroup of adult patients given a 0.5% epidural bolus of ropivacaine. Like bupivacaine, ropivacaine in adults has a biphasic absorption after epidural administration (8,9). These two anesthetics exhibit a slow absorption phase lasting as long as the elimination phase. Differences in Tmax in various studies of epidural ropivacaine in adults and children may reflect a number of factors, including direct effects of the local anesthetics on epidural blood flow, effects of general anesthesia on epidural regional blood flow, or effects of age on absorption (20). It would be interesting to more precisely distinguish between the respective effect of general anesthesia and of delayed absorption on this delayed Tmax. However, the necessity of an additional IV injection to perform deconvolution renders this procedure difficult to perform in young children.

Bupivacaine is currently the most commonly used drug for epidural infusion in children. In considering the relative risks and benefits of ropivacaine versus bupivacaine for continuous epidural infusion, it is relevant to compare bupivacaine’s CL to ropivacaine’s CL among infants and children of different ages. Like most other authors, we did not correct CL for bioavailability because bupivacaine and ropivacaine absorption from the epidural space is considered complete (8,9). The CLs reported for ropivacaine in this study range from 4.26 mL · min-1 · kg-1 in the infants to 6.15 mL · min-1 · kg-1 in the young children. In separate studies, the CL for ropivacaine after single-shot caudal administration in children has been reported as 7.4 mL · min-1 · kg-1 and 7.6 mL · min-1 · kg-1 (12,13). The CL for bupivacaine at 10 mL · min-1 · kg-1 in children after a single-shot caudal block and 11 mL · min-1 · kg-1 for single lumbar epidural bolus is more than the reported CL for ropivacaine by these modes of administration (15,16). However, these authors studied only patients older than 12 months of age. Mazoit et al. (21) reported a CL of 7.1 mL · min-1 · kg-1 for bupivacaine in infants given a single-shot caudal block. Thus, for ropivacaine, as for bupivacaine, CLs in infants are less than those for children. With allowance for differences in study design, methods of pharmacokinetic analysis, and age limits in these studies, the provisional conclusion is that at each age, the CL of bupivacaine is slightly more than that of ropivacaine. From the available information, it is not possible to conclude whether or not the greater CL of bupivacaine compared with ropivacaine would offset the decreased systemic toxicity of ropivacaine, resulting in a similar therapeutic index for the two drugs when given by infusion.

For some drugs, infants and young children have an enhanced capacity to clear drugs compared with neonates and older children; this capacity may partly be caused by their increased proportion of liver mass to body mass (22). In the case of ropivacaine, however, the significantly decreased CL that we found in infants compared with young children may be related to the comparatively delayed maturation of the hepatic enzyme system cytochrome P1A2, which converts ropivacaine to 3-OH ropivacaine (23). Another possible reason for our decreased CLs may be related to the duration of the anesthesia. Our study involved lower extremity, lower abdominal, and pelvic surgery lasting longer than one hour. Prolonged periods of general anesthesia may both delay uptake of drug into the plasma and diminish CL of drug by the liver (24).

Local anesthetic toxicity dose or plasma concentration versus effect relationships for children cannot be determined (for ethical reasons) with the IV infusion methodology used for adult volunteers (3). As a surrogate measure to compare the age dependence of toxicity and therapeutic index for ropivacaine and bupivacaine, an infant, adolescent, and adult rat model was developed (25). Ropivacaine was less toxic (larger dose per kilogram to produce respiratory distress or larger lethal dose per kilogram) than bupivacaine at all ages (25). For both bupivacaine and ropivacaine, infant rats had roughly threefold larger weight-scaled lethal dose per kilogram values than adults (25).

In summary, ropivacaine may be a safe alternative to bupivacaine for epidural blocks in infants and toddlers when it is administered as a single epidural dose of 1.7 mg/kg. Further studies are needed to determine whether there are clinically significant differences between ropivacaine and bupivacaine in infants and children with regard to relative potency, sensory selectivity, CL, duration of analgesia after single-shot dosing, or surrogate measures of therapeutic index.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication June 1, 2001.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 2001 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press