Population Pharmacokinetics of Intraperitoneal Bupivacaine Using Manual Bolus Atomization Versus Micropump Nebulization and Morphine Requirements in Young Children
Authors: Meier Petra M. , Pereira Luis M. , Zurakowski David , Nguyen Hiep T. , Munoz-San Julian Carlos , Houck Constance S. 
Published: May 2019

BACKGROUND:
Intraperitoneal (IP) administration of local anesthetics is used in adults and children for postoperative analgesia after laparoscopic surgery. Population pharmacokinetics (PK) of IP bupivacaine has not been determined in children. Objectives of this study were (1) to develop a population PK model to compare IP bupivacaine administered via manual bolus atomization and micropump nebulization and (2) to assess postoperative morphine requirements after intraoperative administration. We hypothesized similar PK profiles and morphine requirements for both delivery methods.

METHODS:
This was a prospective, sequential, observational study. After institutional review board (IRB) approval and written informed parental consent, 67 children 6 months to 6 years of age undergoing robot-assisted laparoscopic urological surgery received IP bupivacaine at the beginning of surgery. Children received a total dose of 1.25 mg/kg bupivacaine, either diluted in 30-mL normal saline via manual bolus atomization over 30 seconds or undiluted bupivacaine 0.5% via micropump nebulization into carbon dioxide (CO2) insufflation tubing over 10–17.4 minutes. Venous blood samples were obtained at 4 time points between 1 and 120 minutes intraoperatively. Samples were analyzed by liquid chromatography with mass spectrometry. PK parameters were calculated using noncompartmental and compartmental analyses. Nonlinear regression modeling was used to estimate PK parameters (primary outcomes) and Mann-Whitney U test for morphine requirements (secondary outcomes).

RESULTS:
Patient characteristics between the 2 delivery methods were comparable. No clinical signs of neurotoxicity or cardiotoxicity were observed. The range of peak plasma concentrations was 0.39–2.44 µg/mL for the manual bolus atomization versus 0.25–1.07 μg/mL for the micropump nebulization. IP bupivacaine PK was described by a 1-compartment model for both delivery methods. Bupivacaine administration by micropump nebulization resulted in a significantly lower Highest Plasma Drug Concentration (Cmax) and shorter time to reach Cmax (Tmax) (P < .001) compared to manual bolus atomization. Lower plasma concentrations with less interpatient variability were observed and predicted by the PK model for the micropump nebulization (P < .001). Adjusting for age, weight, and sex as covariates, Cmax and area under the curve (AUC) were significantly lower with micropump nebulization (P < .001). Regardless of the delivery method, morphine requirements were low at all time points. There were no differences in cumulative postoperative intravenous/oral morphine requirements between manual bolus atomization and micropump nebulization (0.14 vs 0.17 mg/kg; P = .85) measured up to 24 hours postoperatively.

CONCLUSIONS:
IP bupivacaine administration by micropump nebulization demonstrated lower plasma concentrations, less interpatient variability, low risk of toxicity, and similar clinical efficacy compared to manual bolus atomization. This is the first population PK study of IP bupivacaine in children, motivating future randomized controlled trials to determine efficacy.