Anesth Analg 2008; 107:1182-1184
© 2008 International Anesthesia Research Society
doi: 10.1213/ane.0b013e318181bb4d
PEDIATRIC ANESTHESIOLOGY
Pharmacokinetics of Levobupivacaine (2.5 mg/kg) After Caudal Administration in Children Younger Than 3 Years
Luis I. Cortínez, MD*,
Ricardo Fuentes, MD*,
Sandra Solari, MD ,
Paola Ostermann, MD ,
Miguel Vega, MD, and
Hernán R. Muñoz, MD, MSc*
From the *Departamento de Anestesiología y Laboratorio Clínico, Facultad de Medicina, Pontificia Universidad Católica de Chile, and Servicio de Anestesiología, Hospital Josefina Martínez, Santiago, Chile.
Address correspondence and reprint requests to Dr. Luis I. Cortínez, Departamento de Anestesiología, Hospital Clínico Universidad Católica, Marcoleta 367, Santiago, Chile. Address e-mail to licorti{at}med.puc.cl.
Abstract
BACKGROUND: Caudal administration of levobupivacaine (2.5 mg/kg) in children is used frequently in some hospitals. However, no reports of levobupivacaine concentrations have been published with this dosing scheme. We report the results of a study on the pharmacokinetics of levobupivacaine (2.5 mg/kg) after caudal administration in children younger than 3 yr.
METHODS: Ten children, aged 1–36 mo and scheduled for subumbilical surgery were studied under sevoflurane anesthesia. After caudal injection of 0.25% levobupivacaine (2.5 mg/kg), serial venous blood samples were taken for 3 h to measure total plasma concentration levels of levobupivacaine. Median (range) levobupivacaine Cmax and Tmax measured were 1.48 (0.62–2.40) µg/mL and 37 (10–60) min. The highest individual Cmax was observed in a 1-mo-old infant 30 min after caudal block.
CONCLUSIONS: The highest Cmax reached in this study was close to the toxic threshold of adult patients. Although no adverse events have been reported, care must be taken, especially in small infants, after caudal administration of levobupivacaine (2.5 mg/kg).
Levobupivacaine, the s-enantiomer of the racemic bupivacaine, is widely used in caudal epidural blocks for lower abdominal surgery in children. The major advantage of this pure left-isomer is that, while maintaining a similar clinical profile compared with racemic bupivacaine, it has less toxic potential.1,2
In a study of 12 adult healthy volunteers, levobupivacaine total plasma concentration of 2.38 µg/mL was associated with central nervous system symptoms.3 The toxic threshold of levobupivacaine in children is unknown. However, since levobupivacaine clearance has been shown to be markedly reduced in neonates and young infants, lower doses are recommended in this population.4
Previous studies in children5,6 have shown that caudal administration of levobupivacaine (2.0 mg/kg) produced highly variable levobupivacaine maximum concentrations that range from 0.4 to 2.1 µg/mL. Higher doses of levobupivacaine (2.5 mg/kg) are frequently used in some hospitals.7,8 However, to the best of our knowledge, no reports of levobupivacaine concentrations have been published with this dose scheme. This information is clinically relevant, since it might help clinicians to better decide the best dose scheme for their patients.
We report the results of a study on the pharmacokinetics of levobupivacaine (2.5 mg/kg) after caudal administration in children younger than 3 yr.
METHODS
After institutional ethics committee approval (School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile) and obtaining informed consent from the parents, 10 children, aged 1–36 mo, were studied. All children were ASA class I or II, and scheduled for subumbilical surgery. Exclusion criteria were blood clotting disorders, local skin infection over the caudal zone, hepatic disorders, renal disorders, or any known adverse effect to the study drugs.
No premedication was given. Anesthesia was induced with 6% sevoflurane in oxygen. Two different venous accesses (22 or 24 gauge), for administration of fluids and medications and for serial blood sampling were obtained. The airway was secured with a laryngeal mask. Anesthesia maintenance was with 2% sevoflurane in 50% N2O and 50% O2. During the perioperative period, standard monitoring with electrocardiogram, noninvasive arterial blood pressure, and pulse oximetry was performed.
After induction of anesthesia, the patient was turned into the left lateral position, and a 22-gauge needle was inserted into the sacral hiatus. After prior negative blood aspiration, a caudal injection of 0.25% levobupivacaine (2.5 mg/kg) administered in <30 s was performed and the time of completion of the injection was considered as time zero. All patients received paracetamol rectally (40 mg/kg).
A successful blockade was defined as a hemodynamic (mean arterial blood pressure, heart rate) change <20% than preinduction values in response to surgical incision. If a child responded with a 20% increase in mean arterial blood pressure or heart rate, fentanyl 1 µg/kg was administered. In the postanesthesia care unit, codeine (0.5 mg/kg) was administered as rescue analgesia if the Children’s and Infant’s Postoperative Pain Scale score was <4.9
Blood Sampling
Serial blood samples of 1 mL were taken 2, 5, 10, 20, 30, 45, 60, 90, 120, and 180 min after caudal administration of levobupivacaine. Blood samples were placed in heparin tubes and stored on ice for posterior analysis. Measurements of total plasma concentration levels of levobupivacaine were performed as previously described by Adams et al.10 The assay’s limit of quantification was 0.1 µg/mL and the coefficient of variation at this limit, 7.5%.
Data Analysis
Levobupivacaine total plasma concentration-time profiles, peak plasma concentration (Cmax), and time to reach Cmax (Tmax) were measured and reported.
RESULTS
Ten patients, 5 female and 5 male, age 10 (1–32) mo, weight 9 (4.5–15) kg, were studied. Patient characteristics and the observed levobupivacaine Cmax and Tmax are shown in Table 1. Caudal block was considered adequate in all patients. Vital signs remained stable throughout the study period in all patients. In the postanesthesia care unit, no child required rescue analgesia and no signs or symptoms suggesting toxicity to local anesthetics were reported.
Of the 100 samples (10 per patient), only 2 were not possible to obtain. The individual plasma concentration– time curves are shown in Figure 1. Median (range) levobupivacaine Cmax and Tmax measured were 1.48 (0.62–2.40) µg/mL and 37(10–60) min. The highest individual Cmax was observed in a 1-mo-infant 30 min after caudal block.
DISCUSSION
Levobupivacaine (2.5 mg/kg) was associated with levobupivacaine concentrations close to the total plasma toxic threshold reported in adult patients.3 These results can be used as a guide for clinicians.
A previous study in infants <3 mo5 showed levobupivacaine maximum concentrations between 0.4 and 1.2 µg/mL after caudal administration of 2.0 mg/kg. Compared with that study, our results show a substantially higher Cmax, which is more than the 25% increase that would be expected from the larger dose alone. This apparent discrepancy is probably within the normal range than can be expected considering the high pharmacokinetic variability present in children.4 This last statement is supported by the results of a previous study of these same authors in children younger than 2 yr. In that study, the authors reported levobupivacaine maximum concentrations between 0.4 and 2.1 µg/mL using the same 2.0 mg/kg dose in children <2 yr.
In adults, the reported toxic threshold of levobupivacaine corresponded to the start of mild central nervous system symptoms.3 It is unlikely that such mild manifestations of drug toxicity would be found in infants and children. Not surprisingly, to the best of our knowledge, no symptoms of toxicity to levobupivacaine (2.5 mg/kg) have been reported in children.
In infants and in adults, it is not known how far above the reported toxic threshold significant side effects do occur. It should be noted, however, that it is the unbound, not total, concentration that is pertinent for toxicity data, and that this concentration is dependent on the  1-acid glycoprotein concentration.11 In infants, the plasma concentration of 1-acid glycoprotein is reduced, suggesting that the risk of systemic local anesthetic toxicity would be increased in this population.11 In addition, previous studies indicate that the half-life of levobupivacaine in infants is longer than in children and adults.4 This means that, if toxic levels are reached, they are likely to remain high for a long period.
In conclusion, although no adverse events have been reported, care must be taken, especially in small infants, after caudal administration of levobupivacaine (2.5 mg/kg).
Footnotes
Accepted for publication April 2, 2008.
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