◊ BACKGROUND:
Comparing the relative potency of new local anaesthetics such as levobupivacaine and ropivacaine with bupivacaine by the minimum local analgesic concentration model has not been described for neonatal spinal anaesthesia. This information is important to compare agents and to determine the most effective spinal dose.
◊ METHODS:
We performed a two-stage study to determine the ED50, the ED95, and the relative analgesic potency of isobaric spinal bupivacaine, levobupivacaine, and ropivacaine in infants. In phase 1, 81 infants were randomized in a Dixon–Massey study to describe the minimum local analgesic dose. In phase 2, a further 70 patients were randomly allocated to receive spinal anaesthesia with doses in the upper dose–response range to define the ED95.
◊ RESULTS:
The ED50 doses for bupivacaine, levobupivacaine, and ropivacaine were estimated by isotonic regression to be 0.30 mg kg–1 [95% confidence interval (CI) 0.25–0.43], 0.55 mg kg–1 (0.50–0.64), and 0.50 mg kg–1 (0.43–0.64), respectively. The ED95, respectively, of bupivacaine, levobupivacaine, and ropivacaine were 0.96 mg kg–1 (95% CI 0.83–0.98), 1.18 mg kg–1 (1.05–1.22), and 0.99 mg kg–1 (0.73–1.50). The relative potency ratios at the ED50 were bupivacaine:levobupivacaine 0.55 (95% CI 0.39–0.88), bupivacaine:ropivacaine 0.61 (0.41–1.00), and levobupivacaine:ropivacaine 1.09 (0.84–1.45).
◊ CONCLUSIONS:
Appropriate doses for infant spinal anaesthesia are 1 mg kg–1 of isobaric 0.5% bupivacaine and ropivacaine and 1.2 mg kg–1 of isobaric 0.5% levobupivacaine.
◊ Reviewed by R. Stienstra, MD, PhD,
Nijmegen, Netherlands
Over the past years, the ED50 of local anaesthetics has been determined using the Dixon-Massey up-done sequential allocation method to compare the relative potencies of the newer drugs levobupivacaine and ropivacaine with their predecessor (racemic) bupivacaine. As compared to traditional dose-response studies, this method requires relatively small numbers of patients. However, as a major drawback the outcome reflects only one point on the dose-response curve, the ED50. The ED50 considerably varied among several studies, e.g. in the obstetric population by 40% for epidural bupivacaine[1],[2], and by 75% for epidural ropivacaine[1],[3].
Using mathematical methods, several authors have extrapolated their ED50 on the dose-response curve in an attempt to compare potencies at clinically relevant concentrations. Given the large variability of the ED50, results have been confusing. Also, the validity of mathematical extrapolation of ED50s has been challenged because it does not take into account the possibility of converging dose-response curves.
The present study aims to shed more light on this controversial topic by using a different approach: After determining ED50s for bupivacaine, levobupivacaine, and ropivacaine, the authors performed a dose-escalation study using four dose levels above the ED50. From the combined results, the ED95 was estimated using a method called isotonic regression as well as by probit regression.
The good thing about this study is that the model, i.e. spinal anaesthesia in infants, is likely less prone to confounding factors and hence variability is smaller as compared to epidural analgesia in labour. The authors also give clear dose recommendations for spinal bupivacaine, levobupivacaine, and ropivacaine based on their results.
However, the methodology used to conclude on potency still raises questions and some statements cause confusion. When looking at the ED95 derived from isotonic regression, bupivacaine (0.96 mg kg-1) and ropivacaine (0.99 mg kg-1) are about equipotent and both are more potent than levobupivacaine (1.18 mg kg-1). In the abstract, the authors state this but not the results obtained by probit regression on which their dose recommendation is based. The description of the results further confuses by amazing statements such as “Bupivacaine is also estimated to be more potent than the other two agents at the ED95 doses, with an ED95 0.81 times that of levobupivacaine and 0.97 times that of ropivacaine.” To conclude on greater potency from a 3% difference seems rather futile and not very convincing. In the first two sentences of the discussion the ED50s and ED95s of levobupivacaine and ropivacaine are mixed up; such avoidable mistakes add to the readers’ confusion, especially in articles describing such complex methodology. Difficult to interprete is that levobupivacaine is less potent than ropivacaine at the ED95 when using isotonic regression, but more potent when using probit regression. This is due to a more than 20% difference in the estimated potency of ropivacaine between isotonic and probit regression. This means that the mathematical approach used in this study is either still not accurate or not sufficiently reliable to produce univocal results.
◊ References:
[1] Capogna G, Celleno D, Fusco P, Lyons G, Columb M. Relative potencies of bupivacaine and ropivacaine for analgesia in labour. Br J Anaesth 1999; 82:371-373.
[2] Polley LS, Columb MO, Naughton NN, Wagner DS, Van de Ven CJM. Relative analgesic potencies of ropivacaine and bupivacaine for epidural analgesia in labor: Implications for therapeutic indexes. Anesthesiology 1999; 90:944-950.
[3] Polley LS, Columb MO, Naughton NN, Wagner DS, Van de Ven CJM, Cosmas JM, Goralski KH. Releative analgesic potencies of levobupivacaine and ropivacaine for epidural analgesia in labor. Anesthesiology 2003; 99:1354-1358.
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