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Plasma bupivacaine levels (total and free/unbound) during epidural infusion in liver resection patients: a prospective, observational study
  1. Jessica Burjorjee1,
  2. Rachel Phelan1,
  3. Wilma M Hopman2,
  4. Anthony M-H Ho1,
  5. Sulaiman Nanji3,
  6. Diederick Jalink3 and
  7. Glenio B Mizubuti1
  1. 1Department of Anesthesiology and Perioperative Medicine, Faculty of Health Sciences, Queen's University, Kingston, Ontario, Canada
  2. 2Kingston General Hospital Research Institute, Queen's University, Kingston, Ontario, Canada
  3. 3Department of Surgery, Faculty of Health Sciences, Queen's University, Kingston, Ontario, Canada
  1. Correspondence to Dr Jessica Burjorjee, Department of Anesthesiology and Perioperative Medicine, Queen's University Faculty of Health Sciences, Kingston, Canada; Jessica.Burjorjee{at}kingstonhsc.ca

Abstract

Introduction Liver resection patients may be at an increased risk of local anesthetic (LA) toxicity because the liver is essential for metabolizing LA and producing proteins (mainly α1-acid glycoprotein (AAG)) that bind to it and reduce the free (and pharmacologically active/toxic) levels in circulation. The liver resection itself, manipulation during surgery, and pre-existing liver disease may all interfere with normal hepatic protein synthesis and result in an attenuation of the increased AAG (a positive acute-phase protein) that normally occurs postoperatively. The purpose of this study was to determine whether the AAG response is attenuated postoperatively following liver resection and whether patients approach toxicity thresholds with continuous postoperative epidural infusion of bupivacaine.

Methods Prospective, observational study with blood drawn preoperatively, in the postanesthetic care unit, on postoperative day (POD) 2, and prior to discontinuation of epidural analgesia on POD3/POD4. Plasma was analyzed for total and unbound bupivacaine via liquid chromatography–mass spectrometry and AAG via ELISA. Signs/symptoms of local anesthetic systemic toxicity (LAST), pain, and sedation scores were also recorded.

Results For the 19 patients completed, total plasma bupivacaine was correlated with total administered, but unbound levels were not associated with the total administered. Unlike non-hepatectomy surgery where unbound LA plasma levels remain stable (or decrease) with continuous postoperative epidural administration, we observed an overall increase. Several patients approached toxicity thresholds and 47% reported at least one symptom of LAST, but no epidurals were discontinued because of LAST. In contrast to the AAG response reported following major non-liver surgery where AAG levels increase twofold, we observed a reduction until POD2 and the magnitude was proportional to resection weight.

Discussion Our results are supported by the literature in suggesting that major liver resection patients may be at an increased vulnerability for LAST. Factors such as the extent of liver disease, resection and intraoperative blood loss should be considered when using continuous postoperative epidural infusion of bupivacaine and vigilance should be used in monitoring, for signs/symptoms of LAST, even for those subtle and non-specific. Future research will be required to verify these findings.

Trial registration number NCT03145805.

  • pain, postoperative
  • drug-related side effects and adverse reactions
  • anesthesia, local

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information. The protocols for analyses of blood levels of unbound and total bupivacaine and alpha-1-acid glycoprotein have been uploaded as supplemental material along with the corresponding data resulting from the analyses.

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Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information. The protocols for analyses of blood levels of unbound and total bupivacaine and alpha-1-acid glycoprotein have been uploaded as supplemental material along with the corresponding data resulting from the analyses.

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Footnotes

  • Contributors JB: conceptualization, methodology, investigation, formal analysis, data curation, project administration, supervision, writing of the original draft, writing including review, edit, and approval of the final manuscript; as guarantor, accepts full responsibility for the finished work and the conduct of the study, had access to the data, and controlled the decision to publish. RP: methodology, administration, investigation, data curation, formal analysis, writing of the original draft, and writing including review, edit, and approval of the final manuscript. WMH: methodology, formal analysis, writing of the original draft, writing including review, edit, and approval of the final manuscript. AM-HH, SN, DJ: investigation and writing including review, edit, and approval of the final manuscript. GBM: investigation, writing of the original draft, and writing including review, edit, and approval of the final manuscript. All authors: reviewed and edited the manuscript with important intellectual contributions and approved the final version for submission for publication.

  • Funding Provided by the Alison B. Froese Research Fund in Anesthesiology and Perioperative Medicine, Department of Anesthesiology and Perioperative Medicine, Faculty of Health Sciences, Queen’s University.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.