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Canadian Journal of Anesthesia 50:593-598 (2003)
© Canadian Anesthesiologists' Society, 2003
Obstetrical and Pediatric Anesthesia

In children, the addition of epinephrine modifies the pharmacokinetics of ropivacaine injected caudally

[Chez les enfants, l’addition d’épinéphrine modifie la pharmacocinétique de la ropivacaïne administrée en injection caudale]

Luc J. Van Obbergh, MD PhD*, Fabienne A. Roelants, MD*, Francis Veyckemans, MD* and Roger K. Verbeeck, PhD{dagger}

* From the Department of Anesthesiology,
{dagger} and the School of Pharmacy, Université catholique de Louvain, Brussels, Belgium.

Address correspondence to: Prof L.J. Van Obbergh, Department of Anesthesiology, Cliniques St Luc, 101821 Av. Hippocrate, B1200 Brussels, Belgium. Phone: 3227641821; Fax: 3227643699; E-mail: vanobbergh{at}anes.ucl.ac.be


   Abstract
TOP
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Purpose: To describe the modification of the ropivacaine (R) pharmacokinetics produced by the addition of epinephrine (E).

Methods: After Institutional Review Board approval, 18 ASA I boys received a caudal block (1 mL•kg-1) with either plain 0.2% R (Group E-) or with 0.2% R containing E (5 µg•mL-1; Group E+). Venous blood samples were taken at zero, 15, 30, 60, 90, 120, 180, 240, 420, 720, 1440 min after caudal injection. Total R concentration in plasma was determined by high pressure liquid chromatography. Maximal concentration (Cmax) and time to peak concentration (Tmax) were obtained from the data, terminal half-life (T1/2z), clearance (Cl) and volume of distribution (Vd) were estimated by a non-compartmental approach. Subsequently, in order to determine the absorption rate (Ka) and to reduce to number of blood samples, 25 other children, receiving plain R and another group of 25 receiving the E solution were studied using a population approach (NONMEM). A one compartment model with first order absorption was used. The effect of weight, age and E on Cl, Vd and Ka was estimated.

Results: Cmax was significantly lower in Group E+ (0.93 mg•L-1 ± 0.29 vs 0.61 mg•L-1 ± 0.28, P = 0.05) and Tmax occurred later (124 min ± 53 vs 47min ± 16, P = 0.003).

Weight was a significant covariate for Cl and Vd while E significantly slowed R Ka [Group I Ka 0.025 min-1 [coefficient of variation (CV) 21%] vs 0.078 min-1 (CV 25%) in Group II].

Conclusion: The addition of E significantly modifies the pharmacokinetics of R injected caudally.


   Introduction
TOP
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
ROPIVACAINE is an amide local anesthetic supplied as a pure enantiomer. This contributes to its decreased cardiotoxicity when compared to bupivacaine.1 Ropivacaine has already been used widely caudally to provide per and postoperative analgesia in infants and children undergoing lower abdominal surgery;2,3 its pharmacokinetics have also been studied in various conditions demonstrating that toxic levels are rarely reached if no intravascular injection occurs.4–6 However, as locoregional anesthesia is usually performed in children under general anesthesia or deep sedation, who are thus unable to report subjective signs of intravascular injection, strategies aiming at detecting early signs of accidental intravascular injection have been developed.7 The addition of epinephrine at the concentration of at least 2.5 µg•mL-1 to the injected solution represents one of these.8 Moreover, it has recently been demonstrated that adding epinephrine 1/400000 to bupivacaine prolongs its systemic absorption when injected caudally.9 The aim of the two studies presented here was to describe the modifications of the ropivacaine pharmacokinetics induced by the addition of epinephrine to the solution.


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
Part 1: two-stage pharmacokinetic study using a non-compartmental approach
After approval of the Ethics Committee and signed informed parental consent, 18 ASA I boys undergoing minor lower abdominal surgery were included in the study. No premedication was given, general anesthesia was induced and maintained with sevoflurane 3 to 4% in an air/O2 mixture delivered with a modified Ayre’s T piece (Mapleson D breathing circuit). Fresh gas flow was adjusted to avoid any rebreathing as shown by capnography. Monitoring consisted in end-tidal CO2 and sevoflurane, electrocardiogram (ECG), and pulse oximetry (AS3 monitor, Datex-Ohmeda, Helsinki, Finland). The children were allowed to breathe spontaneously through a face mask. An iv line was inserted to provide iv fluid maintenance according to Liu’s formula10 and to allow blood sampling.

The children were randomly allocated to receive a caudal block (1 mL•kg-1) with either plain 0.2% ropivacaine (Group E-) or with 0.2% ropivacaine containing epinephrine freshly added to the solution in order to obtain a 1/200000 concentration (5 µg•mL-1; Group E+). The caudal block was performed as already described11 with a 22-gauge iv catheter after skin puncture with a larger needle to avoid any tissue coring. Careful aspiration was performed to exclude iv or intrathecal injection. The ECG waveform and the heart rate were monitored during the slow injection of the local anesthetic solution to detect any accidental iv injection: as the ECG changes caused in children by the iv injection of ropivacaine are not yet described, any change in either the ECG waveform or heart rate was to be followed by the immediate interruption of the injection.

Venous blood samples were taken just before and 15, 30, 60, 90, 120, 180, 240, 420, 720, 1440 min after the caudal injection. The collected blood was centrifuged and the plasma was kept frozen at -20°C until further analysis.

Total ropivacaine concentration in plasma was determined by high pressure liquid chromatography (HPLC) following a method already described for other local anesthetic agents.12 This method is briefly summarized here. The plasma (500 µL) containing the ropivacaine was mixed with 1 mL of NaOH and 4 mL of diethylic ether during 15 min. This solution was then centrifuged at 3000 rpm to separate the phases. The diethyl ether was then decanted with 250 µL H2SO4 (0.05 N). The concentrations were determined by HPLC using a Lichrocart column 125-4 Superspher RP-selectB guarded by a precolumn. The mobile phase was a KH2PO4 buffer adjusted to a pH of 5.8 with NaOH (5 N), pumped at 1 mL•min-1. Detection was performed with a UV detector at 208 nm wavelength. Bupivacaine (50 µL of a 10 µg•mL-1 solution) was used as internal standard. The quantification limits were 25 ng•mL-1, with a precision of 6.7% at 50 ng•mL-1 and 2.7% at 1000 ng•mL-1.

Maximal plasma concentration (Cmax) and time to peak plasma concentration (Tmax) were obtained directly from the data. Terminal half-life (T1/2z), clearance (Cl) and volume of distribution (Vd) were estimated by a non-compartmental approach as described by Gabrielsson13 using WinNonLin 1.5 (standard edition; Pharsight Co, Mountain View, CA, USA).

Part 2: population analysis using NONMEM
The effect of adding epinephrine on the absorption phase was studied using a population approach as it was considered unethical to increase the number of blood samples compatible with an adequate description of this phase when using a classical two-stage approach. Again after approval by the Ethics Committee and signed informed parental consent, 50 additional children were included in this second part of our study. Plain 0.2% ropivacaine was administered to half of them while the others received the same solution with epinephrine (1/200000). The anesthetic technique, caudal block, surgical indications and the technique to measure the concentration of ropivacaine were similar to those described in part 1.

Six to ten blood samples were taken from each patient: at least five were drawn randomly during the first 120 min after injection, as this was the time in which Tmax should occur as determined by the results presented in part 1; while the others were drawn at various times up to the 12th hr. We reduced the volume of the sample to 500 µL and the number of samples to six in the infants to maintain the total volume of sampling below 1 mL•kg-1.

Population kinetics was then determined using NONMEM (version V). A one compartment linear model with first order absorption (ADVAN2) was found to fit our data. Subroutine TRANS 2 was used to calculate the following pharmacokinetic parameter (PK): Cl absorption half-time was calculated assuming that T1/2 abs = 0.693/Ka. The introduction of covariates [age, weight and scaling factor for Ka] was made after visual inspection of the WRES vs the covariate; the covariate was kept in the model when a decrease of the objective function of six (P ~ 0.01) was observed. The different models introduced are summarized in Table IIGo. Vd, Cl and absorption rate (Ka) were estimated using the following exponential interpatient error model:


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  		TABLE II Models used for the population study
 

where PKj is the individual parameter for the j patient (Vd, Cl, Ka), TVPK is the mean population parameter and {eta}j is the independently distributed variable with a mean of zero and a variance {omega}2 and an additive intrapatient error model:


where Cij is the ith measured concentration for the jth patient, Cpred ij is the predicted concentration and {varepsilon}ij is the residual variability randomly distributed with zero mean and a variance {sigma}2.

Randomization was performed for both parts of the study with sealed envelopes to be opened after the inclusion of the child in the study. Using the data from the previous studies summarized in Table IVGo, a power analysis found that a sample size of nine patients per group would result in a power of 80% to detect a modification of 50% of both Cmax and Tmax when P ≤ 0.05 is considered as statistically significant.


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  		TABLE IV Comparison of the ropivacaine pharmacokinetic parameters estimated by this study with those issued from other pediatric studies
 
Student’s t test was used in part 1 to perform between group comparisons. Results are mean ± SD.


   Results
TOP
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
None of the children studied developed any signs of toxicity or intravascular injection.

The results of the non-compartmental approach are summarized in Table IGo. The age, body weight and duration of surgery were similar in both groups. Cmax was significantly lowered by the addition of epinephrine, which also significantly delayed the Tmax (FigureGo). Terminal half-life, Cl and Vd were not modified by the addition of epinephrine.


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  		TABLE I Results of the first part of the study
 


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  		FIGURE Concentration vs time curves of children receiving caudal 0.2% ropivacaine (2 mg•kg-1) either with (E+ Group) or without epinephrine (E- Group; mean ± SD).

 
Children included in the population analysis were aged from one day to 48 months with a weight ranging from 2.8 to 18 kg. The minimal objective function and the inclusion of the covariate in the model are found in Table IIGo. Introducing the weight divided by the median value of our population (12 kg) into the model modified significantly the estimated values of both Cl and Vd but not Ka; however, age divided by the median age (34 months) had no effect on the fitting for Cl, Vd or Ka. The final introduction of a factor scaling for the presence of epinephrine (ADR = 1) again significantly improved the estimation by modifying the final value of Ka. The results of the final model described by NONMEM are summarized in Table IIIGo. The estimated absorption half-time of plain ropivacaine was nine minutes while the addition of epinephrine increased it up to 27 min.


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  		TABLE III Parameters estimated by NONMEM in the final model
 

   Discussion
TOP
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
This study shows that the addition of epinephrine to ropivacaine injected caudally modifies its pharmacokinetics. We found that adding a vasoconstrictor decreases the Cmax of ropivacaine and delays its absorption from the epidural space as shown by the later occurrence of Tmax and the longer absorption half-time.

Bupivacaine has been widely used to provide caudal analgesia in children. Although toxic concentrations are rarely obtained when a maximum of 1 mL•kg-1 of 0.25% bupivacaine is used, some authors have recommended that epinephrine should be added to facilitate the detection of intravascular injection as this remains a risk for acute intoxication.14 It has recently been shown that the addition of epinephrine (1/400000) to a 0.25% bupivacaine solution did not modify the Cmax nor the Tmax: however the plasma concentrations measured at 360 min were significantly higher when a vasoconstrictor was added and the authors therefore concluded that epinephrine prolonged the systemic absorption of bupivacaine injected into the caudal space.9

Our results with ropivacaine, however, show more noticeable changes. The greater effects of epinephrine on ropivacaine may be due to the fact that ropivacaine is more liposoluble than bupivacaine and has some intrinsic vasoactivity. The slower absorption of ropivacaine from the caudal space when compared to bupivacaine has been described recently.15 Its absorption from the epidural space is slow and has been described as biphasic; this is related to the high partitioning of ropivacaine into fat.16

Although the Tmax observed in the epinephrine-group was similar to those obtained in other studies (Table IVGo), we found a greater Cmax. However, there is a large variation of the latter parameter in each of those previous studies: this may also explain why the difference in ropivacaine Cmax we measured with or without the addition epinephrine was less significant in our study (P = 0.05) than the modification observed for Tmax. This is in accordance with the bupivacaine study where the main effect of adding epinephrine was mainly a longer absorption phase.9

The results we found for Vd and Cl are similar in both parts of our study and are comparable to those found in the two studies describing these parameters.17,18

The Ka of plain ropivacaine calculated by the population approach used in part two is similar to that found by Hansen et al. This parameter was not influenced by weight or age confirming the previously mentioned study;18 although it has been described that the addition of epinephrine to bupivacaine significantly prolonged the duration of the block and that this was greatest in the younger children.19 We found that weight was a significant covariate for Vd and Cl confirming the results of Lonnqvist et al. who described that age did not modify these parameters and that weight was probably the best variable to adjust dosage.5 However, Hansen et al. were able to correlate Cl with age but their population was younger than ours: these authors indeed studied very young infants and their results are probably linked to the immaturity of the hepatic metabolic pathways in these patients. They also found that the percentage of free ropivacaine was a good covariate for Cl in infants.18 We only determined total ropivacaine concentrations as its binding to plasma proteins or red cells should not be influenced by the addition of epinephrine and because the determination of unbound ropivacaine would require larger blood samples and increase the cost of the study.

Finally, as many other teams worldwide, we routinely use a 22-gauge iv cannula to perform a caudal block in infants and children.11 We acknowledge that the use of a styletted needle, such as a lumbar puncture needle, a Crawford epidural needle or a special "caudal" needle, is recommended by many authors. However, it has been shown that the use of a styletted needle does not reduce the risk of tissue coring into the sacral epidural space providing that a small nick in the skin is made prior to insertion of the iv cannula.20 Moreover, using a small iv cannula instead of a needle reduces the risk of intraosseus penetration and injection as well of displacement into a vessel or subarachnoid space during the injection. This should however not modify the pharmacokinetics of the drug injected caudally.

In conclusion, we have described the pharmacokinetic modifications occurring when epinephrine 5 µg•mL-1 is added to ropivacaine injected caudally. Absorption is prolonged and Tmax occurs significantly later; Cmax is also decreased but to a lesser extent. Further studies are required to determine whether adding epinephrine to ropivacaine results in a prolonged duration of action and whether it effectively helps in detecting an iv injection.


   Footnotes
 
Financial support was provided by departmental and institutional resources.

Revision received January 14, 2003. Revision received March 24, 2003. Accepted for publication September 24, 2002.


   References
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 Introduction
 Methods
 Results
 Discussion
 References
 
1 Markham A, Faulds D. Ropivacaine. A review of its pharmacology and therapeutic use in regional anaesthesia. Drugs 1996; 52: 429–49.[Medline]

2 Van Obbergh LJ, Veyckemans F. Caudal and epidural anaesthesia with ropivacaine in children. Acta Anaesthesiol Belg 2000; 51: 123–6.[Medline]

3 Khalil S, Campos C, Farag AM, Vije H, Ritchey M, Chuang A. Caudal block in children. Ropivacaine compared with bupivacaine. Anesthesiology 1999; 91: 1279–84.[Medline]

4 Ala-Kokko TI, Partanen J, Karinen A, Kiviluoma K, Alahuhta S. Pharmacokinetics of 0.2% ropivacaine and 0.2% bupivacaine following caudal blocks in children. Acta Anaesthesiol Scand 2000; 44: 1099–102.[Medline]

5 Lonnqvist PA, Westrin P, Larsson BA, et al. Ropivacaine pharmacokinetics after caudal block in 1–8 year old children. Br J Anaesth 2000; 85: 506–11.[Abstract/Free Full Text]

6 Bosenberg AT, Thomas J, Lopez T, Huledal G, Jeppsson L, Larsson LE. Plasma concentrations of ropivacaine following a single-shot caudal block of 1, 2 or 3 mg/kg in children. Acta Anaesthesiol Scand 2001; 45: 1276–80.[Medline]

7 Bosenberg AT, Ivani G. Regional anaesthesia – children are different (Editorial). Paediatr Anaesth 1998; 8: 447–50.[Medline]

8 Rowney DA, Doyle E. Epidural and subarachnoid blockade in children. Anaesthesia 1998; 53: 980–1001.[Medline]

9 Hansen TG, Morton NS, Cullen PM, Watson DG. Plasma concentrations and pharmacokinetics of bupivacaine with and without adrenaline following caudal anaesthesia in infants. Acta Anaesthesiol Scand 2001; 45: 42–7.[Medline]

10 Liu L. Fluid management. In: Ryan JF, Coté CJ, Todres ID, Goudsouzian N (Eds.). A Practice of Anesthesia for Infants and Children. Philadelphia: WB Saunders; 1993: 171–83.

11 Veyckemans F, Van Obbergh L, Gouverneur JM. Lessons from 1100 pediatric caudal blockade in a teaching hospital. Reg Anesth 1992; 17: 119–25.[Medline]

12 Sattler A, Kramer I, Jage J, Vrana S, Kleemann PP, Dick W. Development of a HPLC-system for quantitative measurement of lidocaine and bupivacaine in patients plasma during postoperative epidural pain therapy. Pharmazie 1995; 50: 741–5.[Medline]

13 Gabrielsson J, Weiner D. Pharmacokinetic concepts. In: Gabrielsson J, Weiner D (Eds.). Pharmacokinetic and Pharmacodynamic Data Analysis: Concepts & Applications, 3rd ed. Stockholm: Swedish Pharmaceutical press; 2000: 45–174.

14 McGown RG. Caudal analgesia in children. Anaesthesia 1982; 37: 806–18.[Medline]

15 Karmakar MJ, Aun CS, Wong EL, Wong AS, Chan SK, Yeung CK. Ropivacaine undergoes slower systemic absorption from the caudal epidural space in children than bupivacaine. Anesth Analg 2002; 94: 259–65.[Abstract/Free Full Text]

16 Thomas JM, Schug SA. Recent advance in the pharmacokinetics of local anaesthetics. Clin Pharmacokinet 1999; 36: 67–83.[Medline]

17 Habre W, Bergesio R, Johnson C, Hackett P, Joyce D, Sims C. Pharmacokinetics of ropivacaine following caudal analgesia in children. Paediatr Anaesth 2000; 10: 143–7.[Medline]

18 Hansen TG, Ilett KF, Reid C, Lim SI, Hackett P, Bergesio R. Caudal ropivacaine in infants. Population pharmacokinetics and plasma concentrations. Anesthesiology 2001; 94: 579–84.[Medline]

19 Warner MA, Kunkel SE, Offord KO, Atchison SR, Dawson B. The effects of age, epinephrine, and operative site on duration of caudal analgesia in pediatric patients. Anesth Analg 1987; 66: 995–8.[Abstract/Free Full Text]

20 Goldschneider K, Brandom B. The incidence of tissue coring during the performance of caudal injection in children. Reg Anesth Pain Med 1999; 24: 553–6.[Medline]

21 Wulf H, Peters C, Behnke H. The pharmacokinetics of caudal ropivacaine 0.2% in children. Anaesthesia 2000; 55: 757–60.[Medline]

22 Luz G, Innerhofer P, Haussler B, Oswald E, Salner E, Sparr H. Comparaison of ropivacaine 0.1% and 0.2% with bupivacaine 0.2% for single-shot caudal anaesthesia in children. Paediatr Anaesth 2000; 10: 499–504.[Medline]




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