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Anesth Analg 2002;94:259-265
© 2002 International Anesthesia Research Society

PEDIATRIC ANESTHESIA

Ropivacaine Undergoes Slower Systemic Absorption from the Caudal Epidural Space in Children than Bupivacaine

Manoj K. Karmakar, FRCA*, Cindy S. T. Aun, MD*, Eliza L. Y. Wong, MPH*, April S. Y. Wong, BSc*, Simon K. C. Chan, FANZCA*, and Chung K. Yeung, MD{dagger}

*Department of Anesthesia and Intensive Care and {dagger}Department of Surgery, Pediatric Surgical Division, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong

Address correspondence and reprint requests to Manoj K. Karmakar, FRCA, Associate Professor, The Chinese University of Hong Kong, Department of Anesthesia and Intensive Care, Prince of Wales Hospital, Shatin, New Territories, Hong Kong. Address e-mail to karmakar{at}cuhk.edu.hk


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
We compared the systemic absorption of ropivacaine and bupivacaine after caudal epidural administration in children. Twenty ASA physical status I or II children aged 1–7 yr undergoing elective hypospadias repair were randomized after the induction of general anesthesia to receive a single caudal epidural injection of 2 mg/kg of either ropivacaine 0.2% (R) or bupivacaine 0.2% (B) in a double-blinded fashion. Peripheral venous blood samples (1 mL) were obtained before and 1, 5, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, and 120 min after the caudal injection. The total R and B concentration was measured in plasma by using high-performance liquid chromatography. All blocks were successful, and there were no complications. The peak plasma concentration (mean ± SD) (R = 0.67 ± 0.16 and B = 0.73 ± 0.23 µg/mL) and the area under the plasma concentration curve (R = 61.9 ± 20.6 and B = 62.7 ± 18.2 µg · mL-1 · min-1) were comparable between the two study groups. The median (range) time to attain peak plasma concentration was significantly slower in children who received ropivacaine (R = 65 [10–120] min and B = 20 [15–50] min, P < 0.05). We conclude that ropivacaine undergoes slower systemic absorption from the caudal epidural space in children than does bupivacaine.

IMPLICATIONS: We compared the systemic absorption of ropivacaine (0.2%) and bupivacaine (0.2%) after caudal epidural injection of 2 mg/kg in children aged 1–7 yr. Our results show that ropivacaine undergoes slower systemic absorption from the caudal epidural space in children than does bupivacaine.


   Introduction
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 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Ropivacaine (R), the N-propyl homologue of bupivacaine, is a long-acting aminoamide local anesthetic. Compared with bupivacaine (B), which is a racemic mixture, R is a pure S-enantiomer (1). In adults, epidural R produces effective sensory blockade, but the motor blockade is slower in onset (2), less intense, and shorter in duration (1–3). Animal and volunteer studies indicate that R is safer than B in terms of its neurological and cardiac toxicity profile (4–6). Thus R may offer potential benefits when used in children.

R has been safely used for caudal epidural anesthesia in children (7–11). Compared with B, R, when administered via the caudal route, has a quicker onset of action (11) and provides more prolonged postoperative analgesia (11). The motor blockade is less intense (10,12) and shorter in duration (8,10). However, recent trials that have compared the systemic absorption of R and B in children (12,13) have reported conflicting results. After caudal epidural injection of 2 mg/kg of either R (0.2%) or B (0.2%), Luz et al. (12) reported significantly larger peak total and free plasma concentrations of R than B. In contrast, Ala-Kokko et al. (13), using the same dose and concentration of R and B, reported comparable peak plasma concentrations (Cpmax), but the time to peak plasma concentration (Tmax) was significantly shorter after B. In view of these conflicting results, we performed this prospective, randomized, double-blinded study to compare the systemic absorption (rate and extent) of R and B after caudal epidural administration in children.


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
After local research ethics committee approval and written, informed parental consent, 20 healthy boys aged 1–7 yr, ASA physical status I or II, who were scheduled for elective hypospadiasis surgery were randomized by drawing shuffled, coded, opaque envelops to receive a single caudal epidural injection of 2 mg/kg (1 mL/kg) of either R 0.2% (n = 10) or B 0.2% (n = 10). B 0.2% solution was prepared by diluting B 0.5% in 0.9% saline. Children undergoing hypospadias repair were chosen for this study because the surgical procedure in our institute typically takes approximately 2–2.5 h, enabling us to complete all blood sampling for local anesthetic assay with the child anesthetized. Children with preexisting neurological or muscular disorders, skin infection of the caudal area, known allergy to local anesthetics, mental retardation, bleeding tendency, or deranged liver or renal function were excluded from the study.

Patients were fasted preoperatively, and no premedication was prescribed. On arrival to the anesthetic room, routine monitoring was instituted, and anesthesia was induced with sevoflurane and oxygen 100% via a face mask and Jackson Ree’s modification of the T piece. IV access was then established, and 3.3% dextrose and 0.3% saline was infused to replace preoperative fluid deficit and for maintenance. Tracheal intubation was facilitated with vecuronium (0.1 mg/kg) IV. No opioid analgesic was administered before surgical incision to facilitate assessment of the block. Anesthesia was maintained with a mixture of air and oxygen (40%) supplemented with isoflurane (end-tidal concentration, 1%). Standard monitoring, which included pulse oxymetry, electrocardiogram, end-tidal CO2, noninvasive blood pressure, drug concentration, and core body (esophageal) temperature, was used intraoperatively. The lungs were ventilated to maintain normocapnia (end-tidal CO2 concentration, 4.3–4.5 kPa).

The study drug was prepared under aseptic precautions by an anesthesiologist who took no further part in the study. The caudal block was performed by one of the investigators, and the study drug was administered in a double-blinded fashion. The same investigator acted as a blinded observer to record hemodynamic variables after the caudal injection and assessed the success of the block. A single surgeon (CKY) performed the surgical repair (no buccal mucosal graft was involved) on all children studied. A research nurse (ELYW), also blinded to the drug, performed blood sampling for local anesthetic assay and assessed pain and the degree of lower limb motor blockade in the postanesthetic care unit (PACU). The laboratory technician (ASYW) performing the plasma R and B assay was also blinded to the drug administered.

Caudal block was performed with the child in the left lateral position under aseptic precautions by using a 22-gauge IV cannula (AngiocathTM; Becton Dickinson, Sandy, UT), and the study drug (R 0.2% or B 0.2%), 2 mg/kg (1 mL/kg) was administered in aliquots over 1 min, after which the child was returned to the supine position. The time at completion of the caudal injection was noted and recorded as Time 0. Blood pressure and heart rate were recorded before and at 5-min intervals for 20 min after the caudal injection. Surgery commenced at least 15 min after the caudal injection. Response to surgical incision was noted by recording changes in blood pressure, heart rate, and pupillary size. The block was considered successful if there was no change in blood pressure, heart rate, or pupillary size after surgical incision or, if having changed, these indices returned to baseline values. If the block was judged to be successful, the concentration of isoflurane was reduced to an end-tidal concentration of 0.7%. If the block was a failure, IV fentanyl (1 µg/kg) was administered in doses deemed appropriate for supplementary analgesia. Blood loss was estimated and venous hemoglobin level (g/dL) was measured by using a Hemocue hemoglobinometer (Hemocue AB, Ängelholm, Sweden) before and on completion of surgery. At the end of surgery, anesthesia was discontinued, neuromuscular blockade was reversed with neostigmine and atropine, and the patient was tracheally extubated when awake. The patient was then transferred to the PACU for monitoring of vital signs and assessment of pain and the degree of lower limb motor blockade. Each child was observed for 2 h in the PACU.

Pain was assessed with a four-point behavior observer scale (1 = no sign of pain or uneasiness, 2 = uneasy but does not seem to be in pain, 3 = moderate pain, and 4 = severe pain) (14), and rescue analgesia (morphine 20 µg/kg IV) was administered if the pain score was judged to be moderate or severe (14). Lower limb motor blockade was assessed with a modified Bromage scale (0 = no motor block, child moves limbs freely; 1 = inability to raise legs; 2 = inability to flex knees; 3 = no movement possible in legs) (8). Any adverse event during the study period was also recorded.

For measuring venous plasma concentration of total R and B, 1-mL peripheral venous blood samples were drawn from an indwelling IV cannula (forearm or cubital vein) sited in the contralateral arm to that of the IV infusion, before and 1, 5, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, and 120 min after the caudal injection, and collected into prelabeled lithium heparin tubes. In the sampling procedure, the volume of blood equivalent to the dead space of the system was aspirated before, and retransfused after, each blood sampling to avoid contamination or dilution by the previous sample or saline and to limit total blood loss. The blood samples were centrifuged at 3000 rpm for 10 min at room temperature, and the plasma was separated and stored at -70°C until assay as a batch.

A new method was developed to simultaneously assay the venous plasma concentration of total R and B in a single injection by using high-performance liquid chromatography (15), which is a modification of a previously described method of assaying B alone (16). This bioanalytical method allowed the laboratory technician to remain blinded until the assay was completed. The chromatography was achieved with a Novopak C-18 column (Waters Corporation, Milford, MA) with the ultraviolet monitor set at 210 nm. Fixed amounts of internal standard (pentycaine) sodium hydroxide, n-propanaol, and hexane were spiked into a 0.5-mL plasma sample. The hexane phase was transferred to polypropylene tubes and evaporated to dryness under nitrogen at 40°C. The residue was redissolved in hexane and reextracted in phosphoric acid. The mixture was centrifuged, and the hexane phase was discarded while the phosphoric acid phase was injected into the high-performance liquid chromatography system.

Calibration graphs relating peak height ratios and concentrations were linear over the range 10–3000 ng/mL (r = 0.9978 for B and r = 0.9986 for R). The limit of detection for both drugs was 10 ng/mL. The within-day (intraassay) coefficient of variation of the assay varied from 13.84% at 100 ng/mL, 1.84% at 500 ng/mL, and 3.34% at 2000 ng/mL for B to 5.29% at 100 ng/mL, 1.38% at 500 ng/mL, and 3.93% at 2000 ng/mL for R. The between-day (interassay) coefficient of variation was 8.43% at 100 ng/mL, 4.06% at 500 ng/mL, and 9.15% at 2000 ng/mL for B and 5.66% at 100 ng/mL, 4.40% at 500 ng/mL, and 8.14% at 2000 ng/mL for R. The mean relative extraction efficiency ranged from 85.2% to 102.69% between 50 and 3000 ng/mL for B and from 82.83% to 96% between 50 and 3000 ng/mL for R.

The Cpmax and the Tmax for R and B in individual patients were recorded directly from the measured values. The area under the plasma concentration-time curve (AUC) for each patient was calculated with the trapezoidal rule by using NCSS for Windows 1999 (NCSS, Kaysville, UT). Results are presented as mean (SD) (range) unless otherwise stated. Two-tailed Student’s t-tests, Mann-Whitney U-tests, and analysis of variance for repeated measures, with Bonferroni-Dunn for post hoc comparison, were used for intergroup comparison where appropriate. SPSS 10 for Windows (SPSS, Inc., Chicago, IL) was used to perform the above tests. A P value <0.05 was considered statistically significant.


   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
The two study groups were comparable with respect to age, weight, ASA physical status, time from caudal injection to surgical incision, duration of surgery, body temperature, hemoglobin level, total amount of blood loss (Table 1), and cardiovascular changes. All blocks were successful, and there was no complication or clinical evidence of local anesthetic toxicity. Of the 20 patients studied, 18 were finally evaluated. Two patients from the B group were excluded because in one, the blood samples were accidentally frozen before separation of plasma, and in the other, there was an error in adjusting the pH of the mobile phase during sample preparation. Mean plasma concentration-time profiles for total R and B are shown in Figure 1, and Cpmax, Tmax, and AUC for R and B are reported in Table 1. The mean Cpmax and AUC were comparable between the two study groups, but the median Tmax was significantly slower in the R group (65 vs 20 min, P < 0.05). The highest individual Cpmax for R was 1.05 µg/mL in a 1-yr-old and that for B was 1.12 µg/mL in a 7-yr-old, attained at 50 min and 20 min, respectively, after the caudal injection. Once Cpmax was attained, the mean plasma R concentration plateaued, but there was a progressive decline in mean plasma B concentration (Fig. 1), such that B concentrations were smaller than R concentrations at 80, 90, and 120 min (Fig. 1), but they were not statistically significant. On awakening, all patients were pain free in the PACU and did not require any rescue analgesia. There was no evidence of lower limb motor blockade in any patient except one in the B group, who was unable to raise his lower limbs (modified Bromage scale = 1).


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  		Table 1. Patient Characteristics with Clinical and Pharmacokinetic Variables
 


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  		Figure 1. Mean (SD) venous plasma total ropivacaine and bupivacaine concentration after caudal epidural administration of 2 mg/kg of ropivacaine 0.2% or bupivacaine 0.2% in children.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
We compared the systemic absorption of R and B after caudal epidural injection of 2 mg/kg in children aged 1–7 years. Cpmax values of R and B were comparable after the caudal injection, but the Tmax was significantly slower in children who received R. Our results confirm the report of Ala-Kokko et al. (13), that comparable Cpmax values of R and B are attained and that R undergoes slower systemic absorption from the caudal epidural space in children than does B.

There are arteriovenous plasma concentration differences during systemic absorption of local anesthetics (17–20), and the arterial concentration is more representative of the concentration at the site of toxicity in well perfused vital organs (17,20). In children, arterial and peripheral venous (A-V) plasma concentration differences for B are small (approximately 15%–20%) and exist only for the first 15 minutes after caudal injection (19). There are no A-V difference data after R in children. A-V differences of up to 50% have been demonstrated in adult volunteers up to 60 minutes after lumbar epidural R (17). This difference seems to be greater and persists for a longer time than that seen after B (18). Therefore, the venous plasma total R results in our patients must be interpreted with caution when evaluating toxicity because the arterial plasma concentration may have been larger. Moreover, it is the unbound free fraction of a local anesthetic that is thought to produce clinical toxicity, because it can diffuse across biological membranes and bind to receptors at the site of action. We did not measure free levels of R and B because the bioanalytical methodology was not available in our laboratory. Using the same dose as in our study, Luz et al. (12) have reported free R (31.8 ± 26 ng/mL) and B (6.8 ± 1.8 ng/mL) levels in children; these levels are substantially below the threshold (0.6 µg/mL) that produces central nervous system (CNS) toxicity in adult volunteers (6). We measured venous plasma concentration because peripheral venous blood sampling is relatively easy to perform and serial arterial blood sampling was considered too invasive and difficult to justify.

The Cpmax values of R and B measured after the caudal injections were comparable in our study. These values are in agreement with those recently reported by Ala-Kokko et al. (13) and are similar to levels reported in the literature after comparable doses of R (7,12,21–23) and B (12,19,24,25) in children (see Table 2). In contrast, significantly higher Cpmax values of R than B were reported after caudal injection in children by Luz et al. (12). We are unable to explain this difference because patient characteristics and dose were similar.


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  		Table 2. Published Data on the Systemic Absorption Kinetics of Ropivacaine and Bupivacaine After Caudal Epidural Injection in Children
 
As reported by Ala-Kokko et al. (13), we also observed smaller plasma concentrations of B than R at 80, 90, and 120 min. Although the differences were not statistically significant in our study, Ala-Kokko et al. (13), in a larger group of patients, found them to be significantly different. The plasma concentration of local anesthetic after caudal epidural injection depends on its rate of absorption, its volume of distribution, and its rate of elimination (3). The more rapid initial decline in B concentration was attributed to a more rapid initial distribution in tissues caused by its higher lipid solubility compared with R (26) and, thus, a greater volume of distribution of B. It is not known whether there are differences in hepatic clearance between the two drugs that may contribute to the observed difference.

The Cpmax of R was attained significantly later than B in this study. Our Tmax results are comparable with those previously reported for R (12,21–23) and B (12,19,24,25) (see Table 2) and confirm the findings of Ala-Kokko et al. (13) that B is more rapidly absorbed from the caudal epidural space than R. Because the site of injection and the dose were constant in our study and because the ionization constant and plasma protein binding for R and B are almost identical (1), the main factors that affect the rate of systemic uptake are the lipid solubility and vasoactive properties of the drug (3). B is more lipid soluble (1,26) and is taken up more avidly by neural tissue and epidural fat (26) than R. This should theoretically result in slower systemic absorption of B than R because of initial sequestration in the epidural fat, contrary to the results observed in our study. This suggests that the difference in vasoactive property between the two drugs probably outweighs the effect of lipid solubility on the rate of systemic absorption from the caudal epidural space. R decreases epidural blood flow, in contrast to an increase seen after B (27). This intrinsic vasoconstrictor property of R (28,29) may explain the delayed systemic absorption of R.

There was no clinical evidence of toxicity in any of our patients, but one must bear in mind the small sample size in our study and the effects of general anesthesia, which can mask signs of CNS toxicity at the time that the Cpmax values were attained. In this study, the maximum Cpmax after R (1.12 µg/mL) or B (1.05 µg/mL) was well below the threshold, 2.2 µg/mL and 2.1 µg/mL for R and B, respectively, that produces symptoms and signs of CNS toxicity after IV infusion in healthy adult volunteers (6). No comparable data are available for R in children, but the plasma total B concentrations in our patients were below the putative level (2–3 µg/mL) thought to produce neurological toxicity in children. Our data cannot be applied to small infants, because they develop larger Cpmax of local anesthetic compared with toddlers and older children after caudal injection (21). Moreover, lower levels of {alpha}1-acid glycoprotein (24) may account for a higher free fraction of local anesthetics in infants (24).

In conclusion, caudal epidural injection of 2 mg/kg of either R 0.2% or B 0.2% in children aged 1–7 years results in comparable peak venous plasma concentration of total R and B, but R concentrations peak much later than B, confirming results previously reported by Ala-Kokko et al. (13). We believe that the slower systemic absorption of R from the caudal epidural space in children than B is caused by its intrinsic vasoconstrictor property.


   Acknowledgments
 
Supported, in part, by the Department of Anesthesia and Intensive Care, The Chinese University of Hong Kong.

The authors thank the PACU nurses at the Prince of Wales Hospital, The Chinese University of Hong Kong, for their cooperation and assistance during this study. The statistical assistance of Raymond Chung, MPhil, in analyzing the data is also appreciated.


   Footnotes
 
The authors of this article have not received any financial assistance from any drug company or subsidiary to conduct this study, nor do they have any financial interest in the material.

Presented in part at the European Society of Regional Anesthesia, 19th Annual Congress, Rome, September, 2000.


   References
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 Introduction
 Methods
 Results
 Discussion
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Accepted for publication September 13, 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 2002 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press