The area under the plasma concentration curve, AUC(0–60), was 30.0 (4.85–66.6) μg × h × mL−1 in the levobupivacaine group and 60.9 (0.87–202.2) μg × h × mL−1 in the ropivacaine group. The comparison between the 2 CVs showed no statistical difference, with a difference between AUC within the range of maximum variation of 15%: the CV was 0.54 (95% CI: 0.45–0.67) for levobupivacaine and 0.51 (95% CI: 0.42–0.64) for ropivacaine (P = 0.725).
To determine differences in the accumulation rate of the 2 drugs, the fragmented AUCs from T0 to 3, 6, 12, and 24 hours were calculated for the 2 curves, and then the ratio with AUC0-48 (AUC ratio) for each drug was calculated. The plasma concentrations of ropivacaine approached the Cmax significantly faster than those of levobupivacaine (Table 3).
A 1 - compartment open model with an infusion input was fitted to the data obtained during the epidural infusion for all patients enrolled. The median apparent plasma clearance values (CL/F) were estimated to be 0.13 L/h/kg (range: 0.1–1.28 L/h/kg) in the levobupivacaine group and 0.10 L/h/kg (range: 0.06–0.71 L/h/kg) in the ropivacaine group. The terminal half-life was 7.5 hours (1.74–43.4 hours) in the levobupivacaine group and 6.2 hours (1.5–54.6 hours) in the ropivacaine group.
In the study, the value of the clearance of ropivacaine decreases with increasing patient age, whereas the values of clearance of levobupivacaine show a distribution with no correlation with the age of the patient (Fig. 3). The data collected in the study show the aforementioned relationships, but we cannot rule out that these are not related to the large variability in plasma concentrations, the slightly different range of age, and to the size of the study. Therefore, we are not able to exclude that, with a larger sample, the results would be similar to the data already reported in the literature.
Total ropivacaine concentrations were comparable with those reported in previous studies to be tolerated by adult patients: 1.0 to 3.0 μg/mL.32 The maximum value of total ropivacaine concentrations in our study was 4.9 μg/mL. The mean peak value was 1.75 μg/mL (95% CI: 1.541–1.951 μg/mL).
Total levobupivacaine concentrations were lower than the reported toxic systemic threshold of 2.4 to 2.7 μg/mL7,33 except in 1 case, which had a maximum concentration of 3.27 μg/mL. The mean peak value was 1.03 μg/mL (95% CI: 0.908–1.160 μg/mL). We did not find a relationship between the value of the plasma concentration and the onset or type of side effects.
Pain Control and Side Effects
There were no significant differences in NRS, NRSd scores, or in the number of rescue doses between groups (P = 0.209). Adverse effects were mild, with no significant differences between groups.
In this trial, we investigated the pharmacokinetic patterns of levobupivacaine and ropivacaine in adult patients receiving a continuous, 48-hour thoracic epidural infusion for pain management after major abdominal surgery with epidural infusion in the same level (T6–T9) in all patients. There were no differences in the CV of the 2 AUC. The values of ropivacaine clearance decreased as the patient’s age increased; this result could be related to some limitations of our study. During the 48 hours of infusion, plasma concentration did not reach the steady state. Finally, the clinical efficacy and the incidence of adverse effects between groups were equivalent.
The interindividual variability of plasma concentration for levobupivacaine and ropivacaine during thoracic epidural infusions in adults are equivalent; however, the plasma concentration of ropivacaine increased more rapidly than that of levobupivacaine.
Only the clearance of ropivacaine decreased with the increase in patient age. This finding contrasts with previous observations that showed a reduction in the clearance of both ropivacaine and levobupivacaine with correspondence to a patient’s increasing age.34–36 Our data may be related to the large variability in drug plasma concentrations, the slight differences in the age range, and to the size of the study; therefore, we are not able to exclude that with a larger sample, the results would be similar to the data already reported in the literature.
A steady-state concentration was not reached during the 48-hour infusion. This is consistent with previous studies and is presumably attributable to the increase in plasma proteins in the immediate postoperative period. This finding also raises a question about the behavior of ropivacaine and levobupivacaine plasma concentrations during continuous infusions lasting more than 48 hours, especially regarding side effects and local anesthetics systemic toxicity. Finally, equipotent concentrations of levobupivacaine and ropivacaine produced no differences in clinical efficacy, as expected, or in the incidence of adverse effects between groups.
The analysis of the CV (which represents the dispersion of plasma concentration from the median value) revealed that interindividual variability was the same for both drugs. Thus, the manageability of ropivacaine and levobupivacaine in terms of interindividual variability in systemic exposure can be considered equivalent.
In both groups, we observed a continuous, progressive increase in plasma concentration during the infusion, without a steady state being reached. The clearance (CL/F) of ropivacaine was slightly lower than that of levobupivacaine, as would be expected from ropivacaine’s shorter half-life. Previous studies also report that the clearance of local anesthetics can decrease in relation to patient age.34–36 Our results showed that only the clearance of ropivacaine decreases with the increasing age of the patients, but we are not able to exclude that this result may be related to some limitations of our study; for example, the large variability in plasma concentrations, the slightly different range of age inadequate study size for detecting differences the clearance of local anesthetic.
Analysis of the AUC ratio indicated that ropivacaine tended to approach the Cmax faster than levobupivacaine (Table 3). Total ropivacaine peak concentrations were comparable to those reported in previous studies to be tolerated by adult patients; total levobupivacaine peak concentrations were lower than the reported toxic systemic threshold, except in 1 case. Given the reduced number of side effects observed and the absence of correlation with the value of peak plasma concentration of local anesthetic, it has not been possible to perform a detailed analysis of the toxicity of the 2 molecules.
It is important to emphasize that, given the lack of clear indications about the toxic plasma drug concentration in the literature, the calculation of a therapeutic index for each of the drugs under study is fraught with problems. From this it follows that, at present, it is not possible to obtain precise indications of the greater or lesser manageability (ratio between concentration related to toxic effect and concentration related to efficacy) of drugs relative to each other in term of side effects. Plasma concentrations reported in the literature from case reports and case series have no standard temporal relation to the onset of symptoms. However, to our knowledge, in no randomized trials have authors compared whether one or the other of these 2 drugs more frequently presents concentrations above those for which there are case reports of systemic toxicity.
This information does not allow us to draw definitive conclusions regarding the safety of the analyzed drugs; in fact, we did not find any statistical difference in clinical side effects related to the 2 local anesthetics. Hence, our data confirm the conclusions of the review by Di Gregorio et al.37 in which the authors, who analyzed published cases of toxicity from 1979 to 2009, stated that clinical manifestations of toxicity can be extremely heterogeneous and that there is a real need to establish a clear plasma concentration threshold related to systemic toxicity to allow an exhaustive analysis of the safety profile of local anesthetics. The determination of a plasma concentration threshold with regard to the toxic effects also raises many ethical problems that limit the possibility of performing randomized controlled trials. For this reason, it is important to use alternative methods for evaluating the safety of a local anesthetic, such as the assessment of the variability of its plasma concentrations.
From a clinical point of view, the NRS and NRSd scores remained under 4 and without statistical differences throughout the entire follow-up period. No statistical difference was found between the 2 groups regarding the need for rescue doses, showing the optimal effectiveness of both protocols. Likewise, no statistical difference was found in the onset of side effects between the 2 groups, whether considering the total number or single manifestations.
Some shortcomings of our study should be acknowledged. First, there could be differences in local anesthetic absorption as the result of differences in the distribution of epidural fat. In fact, there are some reports indicating that the absorption of local anesthetics is probably affected by the amount of epidural fat. This fat, in turn, is not equally represented along the epidural space and changes with age.38–40 We tried to reduce this variability by comparing data from a sample without statistical differences in age, and in whom the tip of the epidural catheter was in the same position, but we cannot be sure that there were no differences in epidural fat between the groups receiving the different treatments. It would be interesting to investigate the exact correlation of absorption of local anesthetics in relation to epidural fat.
Second, levobupivacaine and ropivacaine are highly bound to α1 acid glycoprotein (AAG) after surgical stress.41–43 Unfortunately, as the result of difficulties related to laboratory, we did not measure the levels of AAG in our trial. Surgery is known to have an important influence on plasma proteins, especially on the concentrations of albumin and AAG.44 Measurements of AAG concentrations after major surgical procedures have shown that these increase gradually within few hours after the surgical procedures.45 We also find in literature that levels of AAG decrease immediately after surgical procedures before recovery and may not reach concentrations comparable to basal until the second postoperative day.46 Because our period of observation was between 24 and 48 hours postoperatively, we can assume that the changes in AAG values during that period were relatively marginal. Nevertheless, the dosage of AAG would have allowed a more accurate analysis of the pharmacokinetic data than emerged from this study.
Finally, the question of pharmacodynamics effects of local anesthetics administrated was not addressed. This is because the low number of side effects recorded during the study did not allow us to evaluate a correlation between pharmacokinetics and pharmacodynamics.
Manuela De Gregori, Biologist, Pain Therapy Service, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy. E-mail: firstname.lastname@example.org; Simona De Gregori, Unit of Clinical Pharmacokinetics in Transplant and Autoimmune Diseases, Infectious Diseases Department, Clinical Epidemiology and Biometric Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy. E-mail: email@example.com; Cristina Ermanna Minella, MD, Pain Therapy Service, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy. E-mail: firstname.lastname@example.org; Dario Bugada, MD, Anesthesia and Intensive Care I, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy. E-mail: email@example.com; Silvia Bettinelli, MD, Anesthesia and Intensive Care I, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy. E-mail: firstname.lastname@example.org; Chiara Baldi, MD, Anesthesia and Intensive Care I, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy. E-mail: email@example.com; Valeria Rossini, Anesthesia and Intensive Care I. San Gerardo Hospital, Monza, and Department of Experimental Medicine. University of Milan Bicocca, Italy. E-mail: firstname.lastname@example.org; and Luca Ghislanzoni, Anesthesia and Intensive Care I. San Gerardo Hospital, Monza, and Department of Experimental Medicine. University of Milan Bicocca, Italy. E-mail: email@example.com.
The interindividual variability of plasma concentration of levobupivacaine and ropivacaine were equivalent during 48 hours thoracic epidural infusions in adults. As the difference between coefficients of variation is within the 15%, this indicates that the 2 molecules have the same manageability. Only the clearance of ropivacaine decreased in accordance with the patient’s age. These data could be related to some limitations of the study. For both drugs, it was not possible to reach the steady-state concentration during 48 hours of epidural infusion; the behavior of the plasma concentrations of local anesthetics for infusions longer than 48 hours remains subject of debate and would require dedicated studies. Finally, we found no differences in the clinical efficacy or in the incidence of adverse effects between groups.
The manuscript was corrected by the professional proofreading service Anchor English.
Name: Luciano Perotti, MD.
Contribution: This author helped analyze the data and prepare the manuscript.
Attestation: Luciano Perotti approved the final manuscript and attests to the integrity of the original data and the analysis reported in this manuscript.
Name: Maria Cusato, Pharmacist.
Contribution: This author helped design the study, conducted laboratory tests and data analysis, and helped in prepare the pharmacokinetic analysis.
Attestation: Maria Cusato approved the final manuscript.
Name: Pablo Ingelmo, MD.
Contribution: This author helped review the manuscript.
Attestation: Pablo Ingelmo approved the final manuscript.
Name: Thekla Larissa Niebel, MD, PhD.
Contribution: This author helped design the study, collect data, analyze the data, and prepare the manuscript.
Attestation: Thekla Larissa Niebel approved the final manuscript.
Name: Marta Somaini, MD.
Contribution: This author helped collect data.
Attestation: Marta Somaini approved the final manuscript.
Name: Francesca Riva, MD.
Contribution: This author helped collect data.
Attestation: Francesca Riva approved the final manuscript.
Name: Carmine Tinelli, MD.
Contribution: This author helped design the study, and analyze the data and statistics.
Attestation: Carmine Tinelli approved the final manuscript.
Name: José De Andrés, MD, PhD, FIPP, EDRA.
Contribution: This author helped review the manuscript.
Attestation: José De Andrés approved the final manuscript.
Name: Guido Fanelli, MD.
Contribution: This author helped review the manuscript.
Attestation: Guido Fanelli approved the final manuscript.
Name: Antonio Braschi, MD.
Contribution: This author helped review the manuscript.
Attestation: Antonio Braschi approved the final manuscript.
Name: Mario Regazzi, PharmD.
Contribution: This author helped design the study, analyze the data, and prepared the pharmacokinetic analysis.
Attestation: Mario Regazzi approved the final manuscript.
Name: Massimo Allegri, MD.
Contribution: This author helped design the study, collect data, analyze data, and prepare and review the manuscript.
Attestation: Massimo Allegri approved the final manuscript and attests to the integrity of the original data and the analysis reported in this manuscript.
Name: SIMPAR Group.
Contribution: These authors helped design the study, collect data, analyze data, and prepare the manuscript.
Attestation: These authors approved the final manuscript.
This manuscript was handled by: Tony Gin, MD, FRCA, FANZCA.
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