A randomized comparison of plasma levobupivacaine concentrations following thoracic epidural analgesia and subpleural paravertebral analgesia in open thoracic surgery
Continuous subpleural paravertebral analgesia may be an alternative to thoracic epidural analgesia following open thoracic procedures. Data about the pharmacokinetic profile of levobupivacaine after administration to the subpleural paravertebral space is unknown. This randomized study investigated differences in plasma levobupivacaine levels between thoracic epidural and subpleural paravertebral administrations. Forty-four patients scheduled for lobectomy or pneumonectomy were randomly allocated into two groups. A thoracic epidural catheter was inserted at the T5-T7 level preoperatively in one group, while the other group had a catheter inserted by the surgeon under direct vision in the paravertebral space at the level of the thoracotomy. A bolus of 0.25% levobupivacaine at 0.5 mg per kg of body weight was administered before the closure of the thoracotomy. The primary outcome was the plasma level of levobupivacaine at 30, 60 and 120 mins. Based on these results, pharmacokinetic modeling was performed. Secondary outcomes included the quality of pain relief, the need for additional systemic analgesia, hemodynamic instability, complication rates and mobility of the patients. Levobupivacaine plasma levels were without statistical difference 30 min after administration – 0.389 mg.L-1 in the epidural and 0.318 mg.L-1 in the subpleural group (p=0.11). Plasma levels were significantly lower in the subpleural group at 60 (p=0.026) and 120 mins (p=0.006). Maximum concentrations and areas under the curve were higher in the epidural group. The time to achieve maximum plasma concentration was similar in both groups – 27.6 versus 24.2 minutes. The intensity of pain was higher in the subpleural group only at two hours (p=0.03), while the need for additional systemic analgesia was similar in both groups. There was no difference between the groups in postoperative complications, mobility and the incidence of hypotension. Systemic levels of levobupivacaine were low in both thoracic epidural and subpleural paravertebral analgesia after bolus administration of local anesthetic and no symptoms of systemic local anesthetic toxicity were recorded. Dosage of 0.5 mg.kg-1 should be sufficiently safe and effective for providing postoperative analgesia in open thoracic surgery.
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Pharmacokinetic data: Levobupivacaine serum concentrations were measured using liquid chromatography with tandem mass spectrometric detection in positive ESI mode (LC-ESI(+)-MS/MS); mepivacaine was used as the internal standard (IS). Internal standard solution (10 µl, c= 125 ng ml-1 in methanol) and 100 µl of borate buffer (pH= 9.0;0.1 mol l-1) were added to 100 µl of serum sample in a 1.5 ml Eppendorf tube. The solution was shaken for 10 s. Following this, 200 µl of ethyl acetate was added into the mixture and it was vortexed for 30 s. The sample was then centrifuged (9600 g, 90 s) and the supernatant (100 µl) was transferred in order to insert it into an autosampler vial and it was then evaporated to dryness. The residue was diluted with 100 µl of mobile phase (50:50, 0,1% formic acid in water and acetonitrile). The method was developed using Nexera X2 Shimadzu HPLC (Nakagyo-ku, Kyoto, Japan) coupled with AB Sciex QTRAP 5500 (MA, USA). Mobile phase A consisted of 0.1% formic acid in water and mobile phase B consisted of acetonitrile. The analysis was performed on Zorbax Eclipse XDB-C18 column (1.8 µm, 50 x 4.6 mm). The initial LC conditions had a flow rate of 0.5 ml min-1 at a mobile phase composition of 50: 50 (A: B). These conditions were held for 120 s to load the analytes onto the column. At 120 s the mobile phase composition was ramped to 100 % (B) within 78 s and held for 30 s and then returned to initial LC conditions. Quantitation was done using multiple reaction monitoring (MRM) mode to monitor protonated precursor → product ion transition of m/z 288.6 → 140.0 for bupivacaine and 246.6 → 98.2 for mepivacaine. Individual levobupivacaine pharmacokinetic parameters – volume of distribution (Vd), clearance (CL), elimination half-life (t1/2), elimination and absorption rate constant (Ke and Ka), maximum serum concentration (Cmax), time to maximum serum concentration (tmax) and area under the serum drug concentration-time curve (AUC) were calculated in a one-compartmental pharmacokinetic model with first-order absorption and elimination kinetics based on individual demographic and clinical data, and observed levobupivacaine serum levels using MWPharm++ software (MediWare, Prague, Czech Republic). The levobupivacaine population pharmacokinetic model was individualized to maximize the fit of the simulated pharmacokinetic profile curve with observed concentration points in each patient. Secondary outcomes included: Visual Analogue Score (VAS) on the scale 0-10 comparisons between the groups at 1, 2, 6, 12 and 24 hours, mobility of the patients using the AM-PAC „6-click“ score at 1, 2, 6, 12 and 24 hours, comparison of need for pharmacological support of circulation with norepinephrine at 30 mins, 6, 12 and 24 hours after the procedure. Changes in neurological status and Glasgow Coma Scale. The total success rate of regional anesthesia technique and their complications were also recorded.