Recommended doses of Levobupivacaine for TAP Blocks: Development of a pharmacokinetic model and estimation of the risk of symptoms of local anesthetic systemic toxicity

Aims: Tranversus Abdominal Plane (TAP) blocks are widely used for postoperative analgesia following abdominal surgery. In this block, the local anaesthetic (LA) solution is injected between the internal oblique and transverse abdominis muscles. Ultrasound guidance has facilitated anatomical plane identification, increasing TAP block popularity. Despite higher precision using ultrasound guidance, high plasma levels of local anaesthetic and systemic toxicity (LAST) cases have been reported with standard doses of ropivacaine and levobupivacaine. Currently, there are no population pharmacokinetic (PK) models describing levobupivacaine absorption during TAP blocks. Our aim is to characterize levobupivacaine absorption pharmacokinetics with and without epinephrine using a population modeling approach, and estimating the risk of LAST of different dose schemes, based on simulation analysis.

Methods: This secondary PK analysis of levobupivacaine uses data from a previously published study1 . Eleven volunteers underwent ultrasound-guided TAP blocks in two independent occasions; the first one, receiving 20 ml of plain 0.25% levobupivacaine, and the second one, adding epinephrine (5mcg*ml-1) to the anaesthetic solution. Serial venous concentrations were measured for 90 minutes. Plasma concentrations of levobupivacaine were used to estimate PK population parameters, using Nonlinear Mixed Effects Models. Analysis of covariates included the use of epinephrine. Estimated pharmacokinetic parameters of levobupivacaine with and without epinephrine and their variability were used to test different dose schemes in a simulated population of 1000 patients. The associate risk of LAST symptoms was calculated, for two commonly recommended dose schemes of 3.0 mg*kg-1 levobupivacaine with epinephrine and 2.5 mg*kg-1 levobupivacaine without epinephrine.

Results: A 1-compartment first order input and elimination model adequately fit levobupivacaine data. The inclusion of epinephrine effect on Tabs produced a significant decrease in OFV of -20.659 points. An additional effect of epinephrine on levobupivacaine bioavailability was tested producing a further improvement in model fit (∆OFV of – 62.834). The derived model predicts that levobupivacaine dose schemes should be halved from 3 mg*kg-1 with epinephrine to 1.5 mg*kg-1 without epinephrine, to obtain a comparable risk of anaesthetic toxicity symptoms of approximately 0.1%. The distribution of levobupivacaine Cmax values obtained using two commonly recommended dose schemes of 3mg*kg-1 levobupivacaine with epinephrine and 2.5mg*kg-1 levobupivacaine without epinephrine is shown in figure 1.

Figure 1. The red dashed line is the mean Cmax. The green dashed line is the 99th percentile of Cmax distribution. The dashed blue line represents the levobupivacaine toxic threshold (2.62 mcg*mL-1)).

Conclusion: Our results strongly support the addition of epinephrine to the local anaesthetic solution, especially when doses of levobupivacaine > 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. 

References:

1. Corvetto MA, Echevarria GC, De La Fuente N, et al. Comparison of plasma concentrations of levobupivacaine with and without epinephrine for transversus abdominis plane block. Regional anesthesia and pain medicine 2012;37(6):633-7.