003: Is the Current Dosing Regimen of Ropivacaine Administered through Erector Spinae Plane Blocks Safe?

Statement of Purpose: Clinical evidence suggests that erector spinae plane (ESP) blocks are safer and easier to perform than epidural analgesia. However, the optimal dosing regimen is currently unknown as central nervous system (CNS) toxicity has been reported in 83.3% (10/12) of healthy volunteers once peak plasma concentrations (C_max) of 3.4 mg/L (minimum to maximum [3.4 to 5.3]) are reached, following administration of a 10 mg/minute infusion until the development of toxicity or a maximum dose of 250 mg was administered.1 It is unknown if the current dosing regimen with a 150-mg loading dose (LD) results in C_max at or above the threshold for CNS toxicity of 3.4 mg/L. Therefore, the objective of this work was twofold: 1. Develop and verify a ropivacaine population pharmacokinetic (PK) model and 2. Optimize the safety profile of ropivacaine by comparing different dosing regimens in clinical trial simulations.

Description of Methods & Materials: Patients scheduled to undergo thoracic surgery were recruited into an observational PK study. The patients received ESP blocks with ropivacaine 150-mg LD followed by 40 mg every 6 h and 2 mg/h infusion started at 6 h after the LD. Intensive PK sampling with approximately 19 samples per patient was collected up to 12 h after the LD. The structural, stochastic, and covariate models were built stepwise using nonlinear mixed-effects modeling. The model selection process was guided by goodness-of-fit (GOF) statistics, GOF plots, precision, and plausibility in parameter estimates. Covariates were selected stepwise. Visual predictive checks and nonparametric bootstrapping were used to qualify the final model. The final model was used to simulate various dosing regimens.

Data & Results: Data from 15 patients were included. Ropivacaine PK was well described with a 2-compartment model with first-order absorption (ka, 10.2 h-1), apparent clearance (CL/F, 7.0 L/h/70 kg), intercompartmental clearance (Q, 124.4 L/h/70 kg), distribution volumes of the central (V/F, 40.4 L/70 kg) and peripheral (V2, 43 L/70 kg) compartments. Height on ka (-14.1) and allometric scaling were included in the final model. Simulations over 24 h show that the current regimen results in C_max ≥3.4 mg/L in 16.9% of patients. Lowering the LD by 25 to 50% will reduce the risk of potentially toxic levels to 0.3 to 4.5%.

Interpretation, Conclusion or Significance: The potential risk of CNS toxicity with 150 mg LD is high, which was predicted to affect 16.9% of patients from our simulations. Simulations show that lower doses are associated with a reduced risk of CNS toxicity. Therefore, lower doses are recommended and should be prospectively evaluated in a dose-exposure response study with a larger sample size.

Disclosures: AAA is funded through UF/GSK Post-Doctoral Fellowship; All other authors have no conflict of interest to declare.