1 Departments of Anaesthesiology and Pharmacology and Toxicology, University of Oulu and 2 Department of Anaesthesiology, Oulu University Hospital, Oulu, Finland *Corresponding author: Department of Anaesthesiology, Oulu University Hospital, PO Box 21, FIN-90029 OUH, Oulu, Finland
The results have been presented at the Scandinavian Society of Anesthesiology and Intensive Care Medicine annual meeting in Tromssa, Norway, 2001.
Accepted for publication: April 18, 2002
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Methods. Forty children scheduled for elective inguinal surgery were randomized to receive 2 mg kg1 of either 0.75% ropivacaine or 0.5% bupivacaine. Surgical anaesthesia was maintained with mask inhalation of oxygen, nitrous oxide and sevoflurane. Venous blood samples were drawn at regular intervals for up to 2 h and plasma was separated. Total venous plasma concentrations were determined by gas chromatography.
Results. The groups were similar with respect to age, weight and dose of local anaesthetic. The peak plasma concentration achieved was significantly higher in the bupivacaine group compared with the ropivacaine group (2.2 vs 1.2 µg ml1, P=0.025). The time to peak plasma concentration was significantly shorter in the bupivacaine group (24 vs 35 min, P=0.024). The initial distribution half time of bupivacaine was significantly shorter (3.6 vs 6.5 min, P=0.020) compared with that of ropivacaine.
Conclusions. Bupivacaine is more rapidly absorbed from the injection site and leads to higher plasma concentrations than ropivacaine.
Br J Anaesth 2002; 89: 43841
Keywords: anaesthesia; anaesthetic techniques, epidural; anaesthetics local, bupivacaine; anaesthetics local, ropivacaine
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
There are some physicochemical differences between ropivacaine and bupivacaine. They have almost identical dissociation constants, but ropivacaine is marginally less tightly bound to plasma proteins and its apparent lipid solubility is approximately half of that of bupivacaine.1214 Plasma levels of bupivacaine and ropivacaine in children have been previously compared following caudal administration.5 8 There are no comparative data available on their plasma levels following an ilioinguinaliliohypogastric block. This study was undertaken to compare the total venous plasma concentrations of similar doses of ropivacaine and bupivacaine following ilioinguinaliliohypogastric blockade in children.
![]() |
Methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The patients underwent ECG, end-tidal CO2 concentration (E'CO2) monitoring, non-invasive arterial pressure measurements and pulse oximetry. In all cases, anaesthesia was maintained with sevoflurane and nitrous oxide in oxygen by facemask inhalation, with spontaneous ventilation.
After induction of anaesthesia, ilioinguinaliliohypo gastric nerve blockade was performed with a 22-gauge short bevelled needle. The local anaesthetic was injected at a point that was 12 cm medial and inferior to the superior anterior iliac spine under the fascia of the external oblique muscle. If the calculated volume of local anaesthetic was <4 ml, it was diluted with saline up to 4 ml. All blocks were performed by experienced paediatric anaesthetists (J.K., K.K.).
Venous blood samples of 5 ml were drawn for the determination of total drug concentrations at 2, 5, 10, 20, 30, 40, 50, 60 and 120 min after the dose. Care was taken not to exceed 5% of the estimated blood volume of the patient. The blood samples were immediately centrifuged at room temperature, and the plasma was separated and stored at 20°C until analysis.
The total concentrations of ropivacaine and bupivacaine bases in 1 ml of plasma were measured by gas chromatography.15 All samples were measured in duplicates with intra-pair variations (SD) of 4.0 (3.0)% and 3.4 (3.5)% for ropivacaine and bupivacaine, respectively.
The peak measured plasma concentration (Cmax) and the time to reach Cmax (Tmax) were estimated from the individual observed plasma concentration time profiles. The initial distribution and elimination half-lives were calculated from the linear phases of the semilogarithmic concentrationtime curves. The area under the concentrationtime curve (AUC) was calculated from the individual concentrationtime curves according to the trapezoid rule.16 Differences between the groups were compared by the MannWhitney test, with a P-value of <0.05 considered statistically significant. The SPSS for Windows statistical package was used.
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
|
|
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Maximum total venous plasma concentrations of >2 µg ml1 were achieved in 60% of the children in the bupivacaine group and 30% in the ropivacaine group. These concentrations of bupivacaine and ropivacaine are close to the reported maximum tolerated venous plasma concentrations of 2.1 µg ml1 and 2.2 µg ml1, respectively, as evaluated from i.v. administration to healthy volunteers.3 A full dose of 2 mg kg1 is probably not necessary for an ilioinguinaliliohypogastric block, and further studies with efficacy data are required to determine the minimum dose required. Although the mean peak plasma concentration in the bupivacaine group was lower than the generally accepted safe maximum total plasma concentration of 4 µg ml1, a peak concentration of 4.9 µg ml1 of bupivacaine was observed in one child.17 Such a high concentration may suggest that at least part of the injection might have inadvertently been administered intravascularly. However, no adverse effects were noted in any of the children in this study. It should be pointed out, however, that possible seizure activity may have been masked by the general anaesthesia, which is known to increase the threshold for seizures.
There are only limited data available on bupivacaine concentrations following ilioinguinaliliohypogastric blockade. In previous studies, lower mean peak plasma bupivacaine concentrations of 0.79 µg ml1 and 1.35 µg ml1 have been reported.18 19 In the study by Stow and colleagues,18 however, a lower dose of bupivacaine (1.25 mg kg1) was used. In the study by Epstein and coworkers,19 a dose of 2 mg kg1 of 0.250.5% bupivacaine was used, and their study series included younger and smaller children than those in our study. Furthermore, both unilateral and bilateral blocks were induced in their study. There were only eight patients who received unilateral blocks induced with 0.5% bupivacaine similar to those used in our study. Although the volume of local anaesthetic per kg of body weight was similar to ours, the mean peak plasma concentration of bupivacaine was lower (1.45 µg ml1) than that measured in our study. They observed a peak plasma concentration of 2.3 µg ml1 in one patient. This could be explained by the fact that there is generally wide inter-individual variation between the plasma concentrations of local anaesthetics as well as their pharmacokinetic variables.20 Our series of 20 patients included eight patients with a peak plasma concentration of bupivacaine lower than 2 µg ml1. In these patients, the mean peak plasma concentration was 1.3 µg ml1, which is similar to that found in the study of Epstein and colleagues.19
In contrast to ilioinguinaliliohypogastric blockade, equal peak plasma concentrations of bupivacaine and ropivacaine have been measured following a caudal block.8 This has been explained by the lower rate of systemic absorption of bupivacaine from the caudal space. Furthermore, the concentrations of bupivacaine and ropivacaine measured in the present study were three times and twice as high, respectively, than those following caudal block.8 In addition, the times to the peak plasma concentration were shorter for both bupivacaine and ropivacaine than those following a caudal block. It has been shown with bupivacaine that absorption from the caudal space is slower and results in lower plasma concentrations than following ilioinguinaliliohypogastric blockade.18 The absorption rates at different sites of injection are known to be directly related to local blood flow and inversely related to local tissue binding.21 The intrinsic vasoconstrictive effect of ropivacaine may slow down its absorption from the injection site while, in contrast, the vasodilative effect of bupivacaine enhances absorption.22 23 It has been shown that plasma uptake is faster from more vascular areas, such as the intercostal space or the axilla, compared with the caudal space.21 24 A previous study showed that, due to its higher lipid solubility, bupivacaine is more intensively absorbed locally into the caudal space, preventing its systemic absorption.8 Injection into the narrow inter-fascial space may enhance systemic absorption and partly explain the higher plasma concentrations of both ropivacaine and bupivacaine compared with those following injection into the caudal space.
In conclusion, ilioinguinaliliohypogastric blockade with 2 mg kg1 of 0.5% bupivacaine led to a more rapid absorption and higher plasma concentrations than a similar dose of 0.75% ropivacaine. Furthermore, the rate of absorption and the peak plasma concentrations of both drugs were higher than those reported following caudal block.
![]() |
Acknowledgement |
---|
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
2 McClure JH. Ropivacaine. Br J Anaesth 1996; 76: 30007
3 Knudsen K, Beckman M, Suurkula M, Blomberg S, Sjövall J, Edvardsson N. Central nervous and cardiovascular effects of i.v. infusions of ropivacaine, bupivacaine and placebo in volunteers. Br J Anaesth 1997; 78: 50714
4 Shandling B, Steward DJ. Regional analgesia for postoperative pain in pediatric outpatient surgery. J Pediatr Surg 1980; 15: 47780[ISI][Medline]
5 Da Conceicao MJ, Coelho L. Caudal anaesthesia with 0.375% ropivacaine or 0.375% bupivacaine in paediatric patients. Br J Anaesth 1998; 80: 5078[ISI][Medline]
6 Da Conceicao MJ, Coelho L, Khalil M. Ropivacaine 0.25% compared with bupivacaine 0.25% by the caudal route. Paediatr Anaesth 1999; 9: 22933[ISI][Medline]
7 Ivani G, Mereto N, Lampugnani E, et al. Ropivacaine in paediatric surgery: preliminary results. Paediatr Anaesth 1998; 8: 1279[ISI][Medline]
8 Ivani G, Lampugnani E, Torre M, et al. Comparison of ropivacaine with bupivacaine for paediatric caudal block. Br J Anaesth 1998; 81: 2478
9 Ala-Kokko TI, Partanen A, Karinen J, Kiviluoma K, Alahuhta S. Pharmacokinetics of 0.2% ropivacaine and 0.2% bupivacaine following caudal blocks in children. Acta Anaesthesiol Scand 2000; 44: 1099102[ISI][Medline]
10 Koinig H, Krenn CG, Glaser C, et al. The dose-response of caudal ropivacaine in children. Anesthesiology 1999; 90: 133944[ISI][Medline]
11 Lonnqvist PA, Westrin P, Larsson BA, et al. Ropivacaine pharmacokinetics after caudal block in 18 year old children. Br J Anaesth 2000; 85: 50611
12 Rosenberg PH, Kyttä J, Alila A. Absorption of bupivacaine, ethidocaine, lignocaine and ropivacaine into n-heptane, rat sciatic nerve and human extradural and subcutaneous fat. Br J Anaesth 1986; 58: 3104[Abstract]
13 Åkerman B, Hellberg I-B, Trossvik C. Primary evaluation of the local anaesthetic properties of the amino amide agent ropivacaine (LEA 103). Acta Anaesthesiol Scand 1988; 32: 5718[ISI][Medline]
14 Lee A, Fagan D, Lamont M, Ticker G T, Halldin M, Scott DB. Disposition kinetics of ropivacaine in humans. Anesth Analg 1989; 69: 7368[Abstract]
15 Huha T, Ala-Kokko TI, Salomäki T, Alahuhta S. Clinical efficacy and pharmacokinetics of 1% ropivacaine and 0.75% bupivacaine in peribulbar anaesthesia for cataract surgery. Anaesthesia 1999; 54: 13741[ISI][Medline]
16 Matthews JNS, Altman DG, Lampbell MJ, Royston P. Analysis of serial measurements in medical research. Br Med J 1990; 300: 2305[ISI][Medline]
17 Moore DC, Balfour RI, Fitzgibbons D. Convulsive arterial plasma concentrations of bupivacaine and the response to diazepam therapy. Anesthesiology 1979; 50: 4546[ISI][Medline]
18 Stow PJ, Scott A, Phillips A, White JB. Plasma bupivacaine concentrations during caudal analgesia and ilioinguinal iliohypogastric nerve block in children. Anaesthesia 1988; 43: 6503[ISI][Medline]
19 Epstein RH, Larijani GH, Wolfson PJ, Ala-Kokko TI, Boerner TF. Plasma bupivacaine concentrations following ilioinguinal iliohypogastric nerve blockade in children. Anesthesiology 1988; 69: 7736[ISI][Medline]
20 Burm AGL, De Boer AG, Van Kleef JW, et al. Pharmacokinetics of lidocaine and bupivacaine and stable isotope labelled analogues: a study in healthy volunteers. Biopharm Drug Dispos 1988; 9: 8595[ISI][Medline]
21 Tucker GT. Pharmacokinetics of local anaesthetics. Br J Anaesth 1986; 58: 71731[ISI][Medline]
22 Kopacz DJ, Carpenter RL, Mackey DC. Effect of ropivacaine on cutaneous capillary blood flow in pigs. Anesthesiology 1989; 71: 6974[ISI][Medline]
23 Geradini G, Samuelson U, Jernbeck J, Aberg B, Sjöstrand N. Comparison of vascular effects of ropivacaine on isolated rings of human arteries. Acta Anaesthesiol Scand 1995; 39: 7658[ISI][Medline]
24 Tucker GT, Mather LE. Pharmacokinetics of local anaesthetic agents. Br J Anaesth 1975; 48: 21324[Abstract]