Flip-flop kinetics of ropivacaine during continuous epidural infusion influences its accumulation rate

Cusato, Maria; Allegri, Massimo; Niebel, Tekla; Ingelmo, Pablo; Broglia, Monica; Braschi, A.; Regazzi, Mario

doi:10.1007/s00228-010-0927-x

Cited by 21 publications

(26 citation statements)

References 22 publications

(12 reference statements)

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“…However, with continuous EP infusion of the drug total mean plasma concentrations were found to increase continuously [7,9,10] or to plateau for a certain time within the dosage interval and then to increase again [6] , in contrast to the relatively stable mean concentrations found in the present study. Also, when total ropivacaine doses administered were compared, higher mean total ropivacaine plasma concentrations at the end of infusion were achieved after continuous EP infusion according to previous studies [6,7,8,10] than after intermittent infusion in our patients, and these higher concentrations were reported to be mainly within or below the range reported to be safe in adults (1.0-3.0 μg/ml) [10] . Thus, evidently, the concentrations achieved after intermittent infusion in this study were safe.…”

Section: Discussioncontrasting

confidence: 56%

“…The long-acting amide local anesthetic ropivacaine has been used for postoperative epidural (EP) analgesia for several years and its pharmacokinetics in humans after intravenous infusion [1][2][3] , wound infusion [4] , extradural infusion [5] , and during EP administration [6][7][8][9][10] have been demonstrated. The concentration-time profile after EP administration of ropivacaine at fixed time inter-vals or continuous subcutaneous (SC) infusion have not been fully evaluated.…”

Section: Introductionmentioning

confidence: 99%

“…The concentration-time profile after EP administration of ropivacaine at fixed time inter-vals or continuous subcutaneous (SC) infusion have not been fully evaluated. Knowledge of ropivacaine systemic levels is very important in order to ensure a high therapeutic ratio [8][9][10] . Furthermore, the role of ropivacaine on the inflammatory response following surgical trauma is still unclear.…”

Section: Introductionmentioning

confidence: 99%

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Ropivacaine, Interleukin-6 and Tumor Necrosis Factor Alpha Plasma Levels during Intermittent Epidural and Continuous Wound Infusion of Ropivacaine for Analgesia after Hysterectomy or Myomectomy: An Observational Study

Markantonis

Melemeni²,

Markidou³

et al. 2016

Pharmacology

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Background/Aims: The concentration-time profile of the long-acting local anesthetic ropivacaine after epidural (EP) administration at fixed time intervals or continuous subcutaneous (SC) infusion has not been fully evaluated. The objective of this work was to determine total plasma concentrations of ropivacaine and changes in cytokine interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) levels during EP and SC. Methods: In this prospective randomized controlled trial, 18 patients undergoing abdominal hysterectomy or myomectomy were randomly selected to receive ropivacaine either every 6 h via an EP catheter or by continuous wound infusion along the skin incision, after a bolus dose, for 48 h. Total plasma ropivacaine concentrations were measured before the bolus and 2, 4, 8, 24, 48, and 50 h after the bolus using high-performance liquid chromatography-UV and IL-6 and TNF-α levels were measured at 0, 8 and 24 h with ELISA and analyzed statistically. Results: During EP, mean ± SD ropivacaine concentrations were relatively stable up to 50 h postoperatively, that is, 239 ± 89 ng/ml, while during SC, initial concentrations between 2 and 8 h were comparatively lower (101.5 ± 42.9 ng/ml) than 24-50 h concentrations (437.1 ± 206 ng/ml). An increase in IL-6 levels was noted between 0 and 24 h during EP and SC, but TNF-α levels increased slightly, between 0 and 24 h, only during EP. Conclusion: Ropivacaine plasma concentrations with both EP and SC were found to be safe throughout the administration time interval. IL-6 levels increased during the same time interval, while TNF levels varied only slightly.

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Section: Discussioncontrasting

confidence: 56%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Ropivacaine, Interleukin-6 and Tumor Necrosis Factor Alpha Plasma Levels during Intermittent Epidural and Continuous Wound Infusion of Ropivacaine for Analgesia after Hysterectomy or Myomectomy: An Observational Study

Markantonis

Melemeni²,

Markidou³

et al. 2016

Pharmacology

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“…The conversion factor for determining what the ropivacaine dose in mice would equate to in humans is approximately 12:1 [30,31], which means our animal dose would be equivalent to a human dose of 0.027 mg/kg, or a total of 1.89 mg for a 70 kg patient. Mean (total) plasma concentration of ropivacaine of 1.82 mg/l (5.5 μM) has been reported to be present (and well-tolerated) in patients after continuous epidural infusions of 0.2% ropivacaine at a rate of 10 mg/hour for 48 hours after major abdominal or urologic surgery [32], thus indicating the ropivacaine dose used in our study is clinically relevant. Additionally, the concentrations used in cell culture experiments were previously proven to have no effect on the viability of rat lung epithelial and endothelial cells [9] as well as human lung adenocarcinoma cells [26].…”

Section: Discussionmentioning

confidence: 71%

Ropivacaine attenuates endotoxin plus hyperinflation-mediated acute lung injury via inhibition of early-onset Src-dependent signaling

Piegeler

Dull

et al. 2014

BMC Anesthesiol

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BackgroundAcute lung injury (ALI) is associated with high mortality due to the lack of effective therapeutic strategies. Mechanical ventilation itself can cause ventilator-induced lung injury. Pulmonary vascular barrier function, regulated in part by Src kinase-dependent phosphorylation of caveolin-1 and intercellular adhesion molecule-1 (ICAM-1), plays a crucial role in the development of protein-/neutrophil-rich pulmonary edema, the hallmark of ALI. Amide-linked local anesthetics, such as ropivacaine, have anti-inflammatory properties in experimental ALI. We hypothesized ropivacaine may attenuate inflammation in a “double-hit” model of ALI triggered by bacterial endotoxin plus hyperinflation via inhibition of Src-dependent signaling.MethodsC57BL/6 (WT) and ICAM-1 −/− mice were exposed to either nebulized normal saline (NS) or lipopolysaccharide (LPS, 10 mg) for 1 hour. An intravenous bolus of 0.33 mg/kg ropivacaine or vehicle was followed by mechanical ventilation with normal (7 ml/kg, NTV) or high tidal volume (28 ml/kg, HTV) for 2 hours. Measures of ALI (excess lung water (ELW), extravascular plasma equivalents, permeability index, myeloperoxidase activity) were assessed and lungs were homogenized for Western blot analysis of phosphorylated and total Src, ICAM-1 and caveolin-1. Additional experiments evaluated effects of ropivacaine on LPS-induced phosphorylation/expression of Src, ICAM-1 and caveolin-1 in human lung microvascular endothelial cells (HLMVEC).ResultsWT mice treated with LPS alone showed a 49% increase in ELW compared to control animals (p = 0.001), which was attenuated by ropivacaine (p = 0.001). HTV ventilation alone increased measures of ALI even more than LPS, an effect which was not altered by ropivacaine. LPS plus hyperinflation (“double-hit”) increased all ALI parameters (ELW, EVPE, permeability index, MPO activity) by 3–4 fold compared to control, which were again decreased by ropivacaine. Western blot analyses of lung homogenates as well as HLMVEC treated in culture with LPS alone showed a reduction in Src activation/expression, as well as ICAM-1 expression and caveolin-1 phosphorylation. In ICAM-1 −/− mice, neither addition of LPS to HTV ventilation alone nor ropivacaine had an effect on the development of ALI.ConclusionsRopivacaine may be a promising therapeutic agent for treating the cause of pulmonary edema by blocking inflammatory Src signaling, ICAM-1 expression, leukocyte infiltration, and vascular hyperpermeability.

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“…The concentrations of ropivacaine and lidocaine that were effective (1 nM to 1 μM) are clinically relevant and consistent with a recent study which reported a well-tolerated, mean (total) maximal plasma concentration of 1.82 mg/l (5.5 μM) during continuous epidural infusions of 0.2% ropivacaine at a rate of 10 mg/h for 48 h after major abdominal or urologic surgery. 31 …”

Section: Discussionmentioning

confidence: 99%

Endothelial Barrier Protection by Local Anesthetics

et al. 2014

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Background Pulmonary endothelial barrier dysfunction mediated in part by Src-kinase activation plays a crucial role in acute inflammatory disease. Proinflammatory cytokines, such as tumor necrosis factor-α (TNFα), activate Src via phosphatidylinositide 3-kinase/Akt-dependent nitric oxide generation, a process initiated by recruitment of phosphatidylinositide 3-kinase regulatory subunit p85 to TNF-receptor-1. Because amide-linked local anesthetics have well-established anti-inflammatory effects, the authors hypothesized that ropivacaine and lidocaine attenuate inflammatory Src signaling by disrupting the phosphatidylinositide 3-kinase–Akt–nitric oxide pathway, thus blocking Src-dependent neutrophil adhesion and endothelial hyperpermeability. Methods Human lung microvascular endothelial cells, incubated with TNFα in the absence or presence of clinically relevant concentrations of ropivacaine and lidocaine, were analyzed by Western blot, probing for phosphorylated/activated Src, endothelial nitric oxide synthase, Akt, intercellular adhesion molecule-1, and caveolin-1. The effect of ropivacaine on TNFα-induced nitric oxide generation, co-immunoprecipitation of TNF-receptor-1 with p85, neutrophil adhesion, and endothelial barrier disruption were assessed. Results Ropivacaine and lidocaine attenuated TNFα-induced Src activation (half-maximal inhibitory concentration [IC50] = 8.611 × 10−10 M for ropivacaine; IC50 = 5.864 × 10−10 M for lidocaine) and endothelial nitric oxide synthase phosphorylation (IC50 = 7.572 × 10−10 M for ropivacaine; IC50 = 6.377 × 10−10 M for lidocaine). Akt activation (n = 7; P = 0.006) and stimulus-dependent binding of TNF-receptor-1 and p85 (n = 6; P = 0.043) were blocked by 1 nM of ropivacaine. TNFα-induced neutrophil adhesion and disruption of endothelial monolayers via Src-dependent intercellular adhesion molecule-1- and caveolin-1-phosphorylation, respectively, were also attenuated. Conclusions Ropivacaine and lidocaine effectively blocked inflammatory TNFα signaling in endothelial cells by attenuating p85 recruitment to TNF-receptor-1. The resultant decrease in Akt, endothelial nitric oxide synthase, and Src phosphorylation reduced neutrophil adhesion and endothelial hyperpermeability. This novel anti-inflammatory “side-effect” of ropivacaine and lidocaine may provide therapeutic benefit in acute inflammatory disease.

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Flip-flop kinetics of ropivacaine during continuous epidural infusion influences its accumulation rate

Cited by 21 publications

References 22 publications

Ropivacaine, Interleukin-6 and Tumor Necrosis Factor Alpha Plasma Levels during Intermittent Epidural and Continuous Wound Infusion of Ropivacaine for Analgesia after Hysterectomy or Myomectomy: An Observational Study

Ropivacaine, Interleukin-6 and Tumor Necrosis Factor Alpha Plasma Levels during Intermittent Epidural and Continuous Wound Infusion of Ropivacaine for Analgesia after Hysterectomy or Myomectomy: An Observational Study

Ropivacaine attenuates endotoxin plus hyperinflation-mediated acute lung injury via inhibition of early-onset Src-dependent signaling

Endothelial Barrier Protection by Local Anesthetics

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