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Population Pharmacokinetics of Intraperitoneal Bupivacaine Using Manual Bolus Atomization Versus Micropump Nebulization and Morphine Requirements in Young Children

Meier, Petra M. MD*; Pereira, Luis M. PhD*; Zurakowski, David MS, PhD*; Nguyen, Hiep T. MD; Munoz-San Julian, Carlos MD*; Houck, Constance S. MD, MPH*

doi: 10.1213/ANE.0000000000004224
Anesthetic Clinical Pharmacology: Original Clinical Research Report
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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.

From the *Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts

Pediatric Urology, Cardon Children’s Medical Center, Mesa, Arizona.

Published ahead of print 4 September 2019.

Accepted for publication April 9, 2019.

Funding: This work was solely supported by the Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, MA.

The authors declare no conflicts of interest.

This was a prospective, observational study, without assignment/enrollment of patients to treatment groups, with reporting performed according to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) consensus.

Institutional review board: Susan Kornetsky, MPH, Director of Clinical Research Compliance, Boston Children’s Hospital, Boston, MA. E-mail: susan.kornetsky@childrens.harvard.edu.

This report was previously presented, in part, at the annual SPA/SPPM meeting, March 2018, Phoenix, AZ, and the American Society of Anesthesiologists meeting, October 2018, San Francisco, CA.

Reprints will not be available from the authors.

Address correspondence to Petra M. Meier, MD, Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children’s Hospital, Harvard Medical School, 300 Longwood Ave, Boston, MA 02115. Address e-mail to petra.meier-haran@childrens.harvard.edu.

Copyright © 2019 International Anesthesia Research Society
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