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BJA Advance Access originally published online on August 12, 2005
British Journal of Anaesthesia 2005 95(4):524-529; doi:10.1093/bja/aei218
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© The Board of Management and Trustees of the British Journal of Anaesthesia 2005. All rights reserved. For Permissions, please e-mail: journal.permissions@oupjournals.org

REGIONAL ANAESTHESIA

Pharmacokinetics of levobupivacaine after caudal epidural administration in infants less than 3 months of age

G. A. Chalkiadis1, B. J. Anderson2, M. Tay1,3, A. Bjorksten1 and J. J. Kelly1,*

1 Department of Anaesthesia and Pain Management, Royal Children's Hospital, Flemington Rd, Parkville, Victoria 3052, Australia. 2 Department of Anaesthesiology, University of Auckland, New Zealand 3 Present address: Department of Paediatric Anaesthesia, KK Women's and Children's Hospital, Singapore

* Corresponding author. E-mail: julian.kelly{at}rch.org.au

Accepted for publication April 4, 2005.


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Background. There are few data describing levobupivacaine pharmacokinetics in infants (<3 months) after caudal administration.

Methods. An open-label study was undertaken to examine the pharmacokinetics of levobupivacaine 2.5 mg ml–1, 2 mg kg–1 in children aged less than 3 months after single-shot caudal epidural administration. Plasma concentrations were determined at intervals from 0.5 to 4 h after injection. A population pharmacokinetic analysis of levobupivacaine time–concentration profiles (84 observations) from 22 infants with mean postnatal age (PNA) 2.0 (range 0.6–2.9) months was undertaken using non-linear mixed effects models (NONMEM). Time–concentration profiles were analysed using a one-compartment model with first-order input and first-order elimination. Estimates were standardized to a 70 kg adult using allometric size models.

Results. Population parameter estimates (between-subject variability) for total levobupivacaine were clearance (CLt) 12.8 [coefficient of variation (CV) 50.6%] litre h–1 70 kg–1, volume of distribution (Vt) 202 (CV 31.6%) litre 70 kg–1, absorption half-life (Tabs) 0.323 (CV 18.6%) h 70 kg–1. Estimates for the unbound drug were clearance (CLfree) 104 (CV 43.5%) litre h–1 70 kg–1, volume of distribution (Vfree) 1700 (CV 44.9%) litre 70 kg–1, absorption half-life (Tabsfree) 0.175 (CV 83.7%) h 70 kg–1. There was no effect attributable to PNA on CL or V. Time to peak plasma concentration (Tmax) was 0.82 (CV 18%) h. Peak plasma concentration (Cmax) was 0.69 (CV 25%) µg ml–1 for total levobupivacaine and 0.09 (CV 37%) µg ml–1 for unbound levobupivacaine.

Conclusions. Clearance in infants is approximately half that described in adults, suggesting immaturity of P450 CYP3A4 and CYP1A2 enzyme isoforms that metabolize levobupivacaine in infants. This lower clearance delays Tmax, which was noted to occur approximately 50 min after administration of caudal epidural levobupivacaine.

Keywords: anaesthetic techniques, regional, caudal; anaesthetics local, levobupivacaine; infants; neonates; pharmacokinetics, levobupivacaine


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
A previous study describing the pharmacokinetics of levobupivacaine 2.5 mg ml–1, 2 mg kg–1 after caudal administration in children younger than 2 yr suggested that the time to peak plasma concentration (Tmax) was reached later in children aged <3 months.1 That study may have underestimated the peak plasma concentration (Cmax) and Tmax because blood was sampled only up to 60 min after levobupivacaine administration. These confounded parameters (Cmax, Tmax) are valuable tools that give us an overview of time–concentration profiles after administration of a drug. However, they depend very much on when samples are taken. If few samples are taken or if samples are missing, accuracy disappears. Knowledge of the true pharmacokinetic parameters (absorption rate constant [KA], volume of distribution [V], clearance [CL]) allows us to predict the profile for a typical individual and estimate confounded parameters with greater precision.

This study was performed to overcome the limitations of the previous report and aimed to describe the pharmacokinetics of levobupivacaine after single-shot administration into the caudal epidural space in infants <3 months of age. This analysis further investigates and quantifies the effect of age using a population-based approach that included size as the primary covariate in an effort to disentangle age-related from size-related factors.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
After approval from the Royal Children's Hospital Ethics Committee, written informed consent was obtained from a parent or legal guardian for their child to enter the study. Levobupivacaine is licensed for use in children >6 months of age in Australia and hence this study constituted an off-label use of the drug, which was approved by the Hospital Ethics Committee. Infants of <3 months postnatal age and ASA class I or II undergoing subumbilical surgery were eligible. Exclusion criteria were previous hypersensitivity to racemic bupivacaine or levobupivacaine, blood clotting disorders, local skin infection over the sacral hiatus or myelomeningocoel.

No premedication was administered. Anaesthesia was induced with sevoflurane, oxygen and nitrous oxide. Anaesthesia was maintained with isoflurane (end-tidal concentration 0.7 MAC) and nitrous oxide 70% in oxygen 30%. Breathing was spontaneous through either a laryngeal mask or a face mask. All caudal injections were performed using a 23 gauge hypodermic needle, which was introduced via the sacrococcygeal membrane. After careful aspiration, a caudal injection of levobupivacaine 2.5 mg ml–1, 2 mg kg–1 was administered over 30 s before commencement of surgery. The time of completion of the injection was recorded as time zero.

Serial blood samples were taken 30, 60, 120, 180 and 240 min after the caudal administration of levobupivacaine. Blood (1 ml) was aspirated from a peripherally sited dedicated 22-G or 24-G i.v. cannula (not in use for i.v. fluid or concomitant medication administration). One millilitre of blood was aspirated from the cannula before sampling to eliminate dead space. After each sample had been obtained, the dead-space aspirate was retransfused and the i.v. cannula then flushed with 1 ml of heparinized saline (heparin 10 units ml–1). If blood could not be aspirated from the i.v. cannula after emergence from anaesthesia, the cannula was not replaced unless clinically indicated. Blood samples were placed immediately into lithium heparin tubes, before being centrifuged within 60 min of collection. Plasma was separated, transferred into plastic tubes and stored at –20°C pending analysis.

Plasma 0.2 ml, H2O 0.2 ml or standard levobupivacaine solution, 0.05 ml, 15 mg litre–1 mepivacaine (internal standard) and 6 ml ethyl acetate were combined in a borosilicate glass tube. The tubes were capped, vortexed for 10 s and centrifuged at 1000 g for 5 min. The ethyl acetate phase was transferred to a second borosilicate tube and evaporated to dryness under nitrogen at 40°C. The residue was reconstituted in 0.025 ml methanol, with the entire sample injected into the gas chromatograph.

The unbound concentration was determined after ultrafiltration of 0.5 ml plasma using the MPS-1 micropartition system using YMT membranes (Amicon) at room temperature. The ultrafiltrate was extracted as for plasma.

The chromatograph used a programmable temperature vaporizer, a 30 m x 0.25 mm BPX50 column (SGE), and nitrogen–phosphorus detection. The method is linear to at least 2000 ng ml–1, with a limit of quantitation of 5 ng ml–1 (coefficient of variation [CV]=12%) and a CV of 4.4% at 200 ng ml–1 (n=8).

Free (unbound) concentration was estimated in one sample from each subject and unbound concentrations were predicted from this unbound percentage.

Pharmacokinetic analysis
A one-compartment model with first-order input and first-order elimination was used. Population parameter estimates were obtained using a non-linear mixed effects model (NONMEM).2 This model accounts for population parameter variability (between and within subjects) and residual variability (random effects) as well as parameter differences predicted by covariates (fixed effects). The population parameter variability in model parameters was modelled by a proportional variance model. An additive term characterized the residual unknown variability. This error model assumes that the residual variability is the same order of magnitude over the whole range of measurements. The population mean parameters, between-subject variance and residual variance were estimated using the first-order conditional estimate method using ADVAN 2 TRANS 2 of NONMEM V. Convergence criterion was three significant digits. The covariance of clearance and distribution volume variability was incorporated into the model. A Compaq Digital Fortran Version 6.6A compiler with Intel Celeron 333 MHz CPU (Intel, Santa Clara, CA, USA) under Microsoft Windows XP (Microsoft, Seattle, WA, USA) was used to compile and execute NONMEM.

The parameter values were standardized for a body weight of 70 kg using an allometric model:3 4

where Pi is the parameter in the ith individual, Wi is the weight in the ith individual and Pstd is the parameter in an individual with a weight Wstd of 70 kg. This standardization allows comparison of neonatal parameter estimates with those reported for adults. The PWR exponent was 0.75 for clearance and 1 for distribution volumes.5–7

The quality of fit of the pharmacokinetic model to the data was sought by NONMEM's objective function and by visual examination of plots of observed vs predicted concentrations. Models were nested and an improvement in the objective function was referred to the {chi}2 distribution to assess significance, e.g. an objective function change (OBJ) of 3.84 is significant at {alpha}=0.05.

The parameter estimates and their variance were used to simulate a time–concentration profile for total levobupivacaine 2.5 mg ml–1 after a caudal dose of 2 mg kg–1. The population predicted mean profile and 5th and 95th centiles were calculated from 1000 simulated profiles.

Cmax (peak concentration) and Tmax (time to peak concentration) were calculated based on individual Bayesian parameter estimates. The following equations were used:

where Ln is the natural logarithm, KA is the absorption rate constant (equivalent to Ln(2)/Tabs; Tabs is the absorption half-life), K is the elimination rate constant and exp the exponential function.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Patient characteristics are shown in Table 1. There were 84 plasma samples obtained from 22 infants. All intended blood samples were aspirated in 12 subjects. In the remainder, aspiration of blood from the i.v. cannula was not possible at various time points. Three of the intended five samples were obtained in three patients and one or two samples in the remainder. The operation type was inguinal hernia repair in all but four patients; two of these had colostomy formation, one had circumcision and one had incision and drainage of perineal abscess.


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  		Table 1 Patient characteristics

 
Parameter estimates are shown in Table 2. Observed time–concentration profiles and the population prediction profile for total and unbound data sets are shown in Figure 1. The population predicted mean profile and 5th and 95th centiles calculated from 1000 simulated profiles are incorporated into Figure 1. The correlation of between-subject variability (BSV) for CL and V was 0.59, CL and absorption half-life (Tabs) 0.99 and V and Tabs 0.68. There was no effect of postnatal age on clearance or volume (Fig. 2A and B) over the age range studied. Figure 3A–C demonstrates the quality of fit for pharmacokinetic data from the total levobupivacaine data set. Individual concentration predictions are based on values of maximum a posteriori Bayesian estimates of the parameters while predicted population concentrations are based on population parameters and covariate information.


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  		Table 2 Parameter estimates for total and unbound levobupivacaine pharmacokinetics using both the allometric and per kilogram size models. BSV is between-subject variability; SE is the standard error of the estimate

 


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  		Fig 1 Time–total levobupivacaine concentration profiles for each patient, with the mean population predicted profile in bold. The dotted lines represent the 5th and 95th centiles calculated from 1000 simulated profiles.

 


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  		Fig 2 (A) Individual predicted total levobupivacaine clearances (CL), standardized to a 70-kg person, from the NONMEM post hoc step, are plotted against postnatal age. (B) Individual predicted volumes of distribution (V), standardized to a 70-kg person, from the NONMEM post hoc step, are plotted against postnatal age. Neither CL nor V is related to infant age within the age range studied.

 


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  		Fig 3 Quality of fit of total levobupivacaine pharmacokinetic data. (A) Population predictions are compared with observed data. The line x=y is the line of identity. (B) Individual Bayesian concentration predictions based on values of the parameters for the specific individual are compared with observed data. (C) The weighted residuals for each subject with values for each subject joined by vertical bars.

 
In patients where all intended samples were aspirated, levobupivacaine total Cmax ranged between 0.4 and 1.2 (mean 0.72, SD 0.23) µg ml–1. The highest levobupivacaine total plasma concentration recorded in any patient was 1.2 µg ml–1. The measured unbound levobupivacaine fraction ranged between 0.054 and 0.20 (mean 0.13, SD 0.04). The mean estimated Tmax, based on parameter estimates for each individual, was 0.82 h (CV 18%) (Fig. 4). The mean estimates for Cmax were 0.69 µg ml–1 (CV 25%) for total levobupivacaine and 0.09 µg ml–1 (CV 37%) for unbound levobupivacaine. A trend line shows a decrease of Tmax with age, but data were too few to confirm this trend.



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  		Fig 4 Estimated values for Tmax, based on parameter estimates for each individual. Tmax tended to decrease with age.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
This study describes the pharmacokinetic profile of levobupivacaine in infants <3 months of age. We report levobupivacaine pharmacokinetic parameters in infants using size as a primary covariate. The estimates for clearance (12.8 litre h–1 70 kg–1, CV 50.6%) are approximately half that described in adults (20.9 [SD 6.8] litre h–1 70 kg–1).8 Volume of distribution is greater than in adults (Vss 56 litre 70 kg–1 [SD 14]),8 consistent with similar observations for bupivacaine.9 Size has considerable impact on the estimation and interpretation of pharmacokinetic parameters in children4 and is often unaccounted for in neonatal and infant pharmacokinetic studies.10 A great many physiological, structural and time-related variables scale predictably within and between species, with weight exponents of 0.75, 1 and 0.25 respectively.5 We have used these ‘1/4 power models’ in the present study rather than centred weight, or some other function of weight, because the 1/4 power models have sound biological principles. West and colleagues67 have used fractal geometry to mathematically explain this phenomenon. The 3/4 power law for metabolic rate was derived from a general model that describes how essential materials are transported through space-filled fractal networks of branching tubes. These design principles are independent of detailed dynamics and explicit models and should apply to virtually all organisms.

By choosing weight as the primary covariate, the secondary effects of postnatal age could be investigated. We were unable to demonstrate an effect of age within this current cohort because of small sample size limited to a narrow age range.11 Clearance in this cohort of infants was reduced compared with adults, but the time course of maturation could not be quantified. Levobupivacaine is metabolized by the CYP3A4 and CYP1A2 isoforms to desbutyl levobupivacaine and 3-hydroxy levobupivacaine, respectively. Data from ropivacaine, an amide anaesthetic that is metabolized by these same enzymes, suggests that clearance approaches adult values within the first 6–12 months of life.10 Tmax after single-shot caudally administered levobupivacaine is reached later in young infants.1 The absorption half-life is similar to that described after paediatric epidural bupivacaine (0.33 h),12 suggesting that reduced clearance contributes to a delayed Tmax. The impact of caudal space vascularity, epidural fat or caudal absorptive surface area differences between infants and older children is undefined. Age did not affect the disposition or systemic absorption of bupivacaine in 20 adult male patients aged 22–81 yr.13

Levobupivacaine is highly bound to {alpha}1 acid glycoprotein (AAG).14 AAG is an acute-phase reactant that increases after surgical stress. Mean preoperative AAG concentrations of 0.38 (SD 0.16) mg ml–1 increased to 0.76 (0.18) mg ml–1 in infants by day 4 after surgery and stayed at that concentration through to day 7.15 This causes an increase in total plasma concentrations for low to intermediate extraction drugs, such as levobupivacaine.16 The unbound concentration, however, will not change because clearance of the unbound drug is affected only by the intrinsic metabolizing capacity of the liver.17 Any increase in unbound concentrations observed during long-term epidural is attributable to reduced clearance rather than AAG concentration.18 19 We were unable to measure sequential unbound concentrations because of restrictions on the amount of blood (5 ml) that could be sampled from infants. However, the time to reach peak AAG concentrations after surgery is long (4 days) compared with our short duration of sampling (4 h).

In conclusion, we have demonstrated that the clearance of levobupivacaine after single-shot caudal administration in infants <3 months of age is approximately half that described in adults, suggesting immaturity of P450 CYP3A4 and CYP1A2 enzyme isoforms that metabolize levobupivacaine. This lower clearance delays Tmax, which was noted to occur approximately 50 min after administration of caudal levobupivacaine. Plasma concentrations achieved suggest that 2 mg kg–1 levobupivacaine administered via the caudal route as a single dose is safe to use in this age group. We were unable to detect a relationship between postnatal age and clearance of levobupivacaine in this population.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
1 Chalkiadis GA, Eyres RL, Cranswick N, Taylor RH, Austin S. Pharmacokinetics of levobupivacaine 0.25% following caudal administration in children under 2 years of age. Br J Anaesth 2004; 92: 218–22[Abstract/Free Full Text]

2 Sheiner LB, Beal SL. NONMEM Users Guide. San Francisco: Division of Pharmacology, University of California, 1979

3 Holford NHG. A size standard for pharmacokinetics. Clin Pharmacokinet 1996; 30: 329–32[Web of Science][Medline]

4 Anderson BJ, Meakin GH. Scaling for size: some implications for paediatric anaesthesia dosing. Paediatr Anaesth 2002; 12: 205–19[CrossRef][Web of Science][Medline]

5 Peters HP. Physiological correlates of size. In: Beck E, Birks HJB, Conner EF, eds. The Ecological Implications of Body Size. Cambridge: Cambridge University Press, 1983; 48–53

6 West GB, Brown JH, Enquist BJ. A general model for the origin of allometric scaling laws in biology. Science 1997; 276: 122–6[Abstract/Free Full Text]

7 West GB, Brown JH, Enquist BJ. The fourth dimension of life: fractal geometry and allometric scaling of organisms. Science 1999; 284: 1677–9[Abstract/Free Full Text]

8 Simon MJ, Veering BT, Stienstra R, et al. The systemic absorption and disposition of levobupivacaine 0.5% after epidural administration in surgical patients: a stable-isotope study. Eur J Anaesthesiol 2004; 21: 460–70[CrossRef][Web of Science][Medline]

9 Murat I, Montay G, Delleur MM, Esteve C, Saint-Maurice C. Bupivacaine pharmacokinetics during epidural anaesthesia in children. Eur J Anaesthesiol 1988; 5: 113–20[Medline]

10 Anderson BJ, Hansen TG. Getting the best from pediatric pharmacokinetic data. Paediatr Anaesth 2004; 14: 713–5[Medline]

11 Ribbing J, Jonsson EN. Power, selection bias and predictive performance of the Population Pharmacokinetic Covariate Model. Pharmacokinet Pharmacodyn 2004; 31: 109–34.

12 Anderson BJ, Chojnowska E. Pharmacokinetics and the drugs used in paediatric regional anaesthesia. Tech Reg Anaesth Pain Manage 1999; 3: 129–37

13 Veering BT, Burm AG, Vletter AA, van den Heuvel RP, Onkenhout W, Spierdijk J. The effect of age on the systemic absorption, disposition and pharmacodynamics of bupivacaine after epidural administration. Clin Pharmacokinet 1992; 22: 75–84[Web of Science][Medline]

14 Gunter JB. Benefit and risks of local anesthetics in infants and children. Paediatr Drugs 2002; 4: 649–72[Medline]

15 Booker PD, Taylor C, Saba G. Perioperative changes in alpha 1-acid glycoprotein concentrations in infants undergoing major surgery. Br J Anaesth 1996; 76: 365–8[Abstract/Free Full Text]

16 Erichsen CJ, Sjovall J, Kehlet H, Hedlund C, Arvidsson T. Pharmacokinetics and analgesic effect of ropivacaine during continuous epidural infusion for postoperative pain relief. Anesthesiology 1996; 84: 834–42[CrossRef][Web of Science][Medline]

17 Benet LZ, Hoener BA. Changes in plasma protein binding have little clinical relevance. Clin Pharmacol Ther 2002; 71: 115–21[CrossRef][Web of Science][Medline]

18 Anderson BJ, McKee AD, Holford NH. Size, myths and the clinical pharmacokinetics of analgesia in paediatric patients. Clin Pharmacokinet 1997; 33: 313–27[Web of Science][Medline]

19 Rapp HJ, Molnar V, Austin S, et al. Ropivacaine in neonates and infants: a population pharmacokinetic evaluation following single caudal block. Paediatr Anaesth 2004; 14: 724[CrossRef][Medline]


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