title: Levobupivacaine absorption pharmacokinetics with and without epinephrine during TAP block: analysis of doses based on the associated risk of local anaesthetic toxicity.
abstract: OBJECTIVE
  Cases of local anaesthetic systemic toxicity (LAST) periodically occur following transversus abdominal plane (TAP) blocks. The aim of this study was to characterize levobupivacaine absorption pharmacokinetics, with and without epinephrine, and estimate the risk of LAST, based on a previously reported toxic threshold.
  
  
  METHODS
  Previously reported data from 11 volunteers receiving ultrasound-guided TAP blocks with and without epinephrine on two independent occasions were analysed. Serial venous concentrations were measured for 90 min. A pharmacokinetic analysis was performed using the NONMEM statistical programme. The use of epinephrine in the solution was included in the analysis of covariates. The associated risk of LAST symptoms associated with different levobupivacaine dose schemes with and without epinephrine was estimated in 1000 simulated subjects.
  
  
  RESULTS
  A one-compartment first-order input and elimination model adequately fit the levobupivacaine data. Epinephrine prolonged the levobupivacaine absorption half-life {4.22 [95 % confidence interval (CI) 2.53-6.50] vs. 7.02 [95 % CI 3.74-14.1]; p < 0.05} and reduced its relative bioavailability (0.84; 95 % CI 0.72-0.97; p < 0.05) The derived model predicts that levobupivacaine dose schemes should be halved from 3 mg kg(-1) body weight with epinephrine to 1.5 mg kg(-1) without epinephrine to obtain a comparable risk of anaesthetic toxicity symptoms of approximately 0.1 %.
  
  
  CONCLUSIONS
  Our results strongly support the addition of epinephrine to the local anaesthetic solution, especially when doses of levobupivacaine of >1.5 mg kg(-1) are required. Recommendations regarding the maximum allowable doses of local anaesthetics should consider population analysis to determine safer dosage ranges.
authors.affiliation: División de Anestesiología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Marcoleta 367, 8330024, Santiago, Chile.
authors.forename: P
authors.initials: P
authors.lastname: Miranda
authors.affiliation: División de Anestesiología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Marcoleta 367, 8330024, Santiago, Chile.
authors.forename: M A
authors.initials: MA
authors.lastname: Corvetto
authors.affiliation: División de Anestesiología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Marcoleta 367, 8330024, Santiago, Chile. fernando.altermatt@gmail.com.
authors.forename: Fernando R
authors.initials: FR
authors.lastname: Altermatt
authors.affiliation: División de Anestesiología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Marcoleta 367, 8330024, Santiago, Chile.
authors.forename: A
authors.initials: A
authors.lastname: Araneda
authors.affiliation: División de Anestesiología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Marcoleta 367, 8330024, Santiago, Chile.|Department of Anaesthesiology, New York University School of Medicine, New York, NY, USA.
authors.forename: G C
authors.initials: GC
authors.lastname: Echevarría
authors.affiliation: División de Anestesiología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Marcoleta 367, 8330024, Santiago, Chile.
authors.forename: L I
authors.initials: LI
authors.lastname: Cortínez
mesh_terms: D000009:Abdominal Muscles / Q000294:innervation; D000328:Adult; D000779:Anesthetics, Local / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D002045:Bupivacaine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D003198:Computer Simulation; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004837:Epinephrine / Q000494:pharmacology*; D006207:Half-Life; D064368:Healthy Volunteers; D006801:Humans; D000077554:Levobupivacaine; D008297:Male; D008954:Models, Biological; D009407:Nerve Block; D012306:Risk
chemical_list: D000779:Anesthetics, Local; D000077554:Levobupivacaine; D002045:Bupivacaine; D004837:Epinephrine
keywords: Levobupivacaine; Pharmacokinetics; Systemic toxicity; Transversus abdominis plane block