Bupivacaine Levels in Liver Resection Patients

Blood Levels of Bupivacaine in Liver Resection Patients Sited With an Epidural Catheter for Postoperative Pain Control

Bupivacaine is a local anesthetic commonly used to manage postoperative pain. Liver resection patients typically have an epidural catheter placed preoperatively through which they receive a continuous infusion of bupivacaine and hydromorphone for up to 5 days postoperatively. The liver metabolizes bupivacaine, and produces proteins that bind with bupivacaine to take it out of circulation and thereby reduce its toxicity. Because a portion of the liver is being removed due to pre-existing liver disease, investigators hypothesize that liver resection patients have an impaired ability to clear bupivacaine from circulation that may increase their susceptibility to bupivacaine toxicity. To assess this, investigators will measure free and bound bupivacaine in liver resection patients postoperatively to determine whether bupivacaine reaches toxic levels. Investigators will also quantify binding protein levels to determine if these levels are reduced after surgery, which could contribute to the elevated bupivacaine levels in these patients. Finally, investigators will monitor patients for signs and symptoms associated with bupivacaine toxicity.

Study Overview

• Status: Completed
• Conditions: Hepatectomy; Analgesia, Epidural

Detailed Description

This observational study has been approved for ethical compliance by the Queen's University Health Sciences & Affiliated Teaching Hospitals Research Ethics Board. Following signed informed consent, investigators will collect blood samples from 20 liver resection patients preoperatively and then at 3 different time points after their liver surgery at Kingston General Hospital (upon entry to the post-anesthetic care unit [PACU], on postoperative day 2, and immediately prior to discontinuation of the bupivacaine infusion). These blood draws will occur at the same time as standard of care blood draws. Blood will be centrifuged, and plasma will be stored in duplicate at -70°C until all samples are collected. Samples will be shipped to Centre De Recherche, Centre De Hospitalier, de l'Universitie de Montreal (CHUM) in Montreal, Quebec, Canada, for quantification of free and total bupivacaine as well as AGP. In addition to quantifying circulating bupivacaine and AGP concentrations, investigators will also assess postoperative wound pain on a visual analog scale from 0 to 10, and the presence/absence of local anesthetic toxicity symptoms (tremor, tinnitus, dizziness, blurred vision, hypotension and arrhythmia (including bradycardia).6 These will be assessed as close as possible to the blood collection times (preoperatively, upon arrival to the PACU, on postoperative day 2, and immediately prior to discontinuation of the bupivacaine infusion). Finally, demographic and surgical characteristics will be recorded for all participants.

Inclusion criteria are competent ASA I-IV patients 18 years of age and older scheduled for elective liver resection of at least 3 segments who receive epidural bupivacaine infusion for pain control. Exclusion criteria: pregnancy, renal failure requiring dialysis, sepsis, ejection fraction documented as <15%, taking fluvoxamine or itraconazole, and inability to understand and read English.

Investigators have several outcomes of interest in this study. Of primary interest: plasma concentrations of free and bound bupivacaine and AGP at various time points after surgery. Additional outcomes of interest are pain scores and signs or symptoms of local anesthetic toxicity. Demographic and surgical characteristics will be collected for each patient. Descriptive, univariate and multivariable analyses will be completed with the assistance of a biostatistician.

• Study Type: Observational
• Enrollment (Actual): 20

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Kingston, Ontario, Canada, K7L2V7
      • Kingston General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Twenty patients over 18 years of age scheduled to undergo elective liver resection surgery and placement of an epidural catheter for continuous bupivacaine infusion to manage pain for 3-5 days postoperatively.

Description

Inclusion Criteria:

• scheduled to undergo elective liver resection surgery
• indicated to be sited with an epidural catheter for bupivacaine infusion for the management of postoperative pain
• competent to provide informed consent
• American anesthesiologists physical classification of I-IV

Exclusion Criteria:

• pregnant
• renal failure requiring dialysis
• sepsis
• ejection fraction documented as <15%
• taking fluvoxamine or itraconazole
• unable to understand or read English

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort
liver resection patients; Liver resection patients sited with an epidural catheter for bupivacaine infusion for 3-5 days postoperatively to manage postoperative pain

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
bound bupivacaine levels-1	plasma bound bupivacaine levels in liver resection patients upon entry to the post anesthesia care unit	1-2 hours following surgery
bound bupivacaine levels-2	plasma bound bupivacaine levels on postoperative day 2.	48 hours following surgery
bound bupivacaine levels-3	plasma bound bupivacaine levels upon discontinuation of bupivacaine infusion (3-5 days postoperatively)	72-120 hours following surgery
unbound bupivacaine levels-4	plasma unbound bupivacaine levels in liver resection patients upon entry to the post anesthesia care unit	1-2 hours following surgery
unbound bupivacaine levels-5	plasma unbound bupivacaine levels on postoperative day 2.	48 hours following surgery
unbound bupivacaine levels-6	plasma unbound bupivacaine levels upon discontinuation of bupivacaine infusion	72-120 hours following surgery
alpha-1-acid glycoprotein levels-(AGP)-1	plasma AGP levels preoperatively	1 hour preoperatively
alpha-1-acid glycoprotein levels-(AGP)-2	plasma AGP levels postoperatively upon entry to the post anesthesia care unit	1-2 hours postoperatively
alpha-1-acid glycoprotein levels-(AGP)-3	plasma AGP levels on postoperative day 2	48 hours postoperatively
alpha-1-acid glycoprotein levels-(AGP)-4	plasma AGP levels upon discontinuation of the bupivacaine infusion 3-5 days postoperatively	72-120 hours postoperatively

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
signs/symptoms of local anesthetic toxicity-1	tremor, tinnitus, dizziness, blurred vision, hypotension and arrhythmia (including bradycardia)-preoperatively	1 hour preoperatively
signs/symptoms of local anesthetic toxicity-2	tremor, tinnitus, dizziness, blurred vision, hypotension and arrhythmia (including bradycardia)-upon entry to the post anesthesia care unit	1-2 hours postoperatively
signs/symptoms of local anesthetic toxicity-3	tremor, tinnitus, dizziness, blurred vision, hypotension and arrhythmia (including bradycardia)-on postoperative day 2	48 hours postoperatively
signs/symptoms of local anesthetic toxicity-4	tremor, tinnitus, dizziness, blurred vision, hypotension and arrhythmia (including bradycardia)-upon discontinuation of bupivacaine infusion-3-5 days postoperatively	72-120 hours postoperatively
surgical site pain-1	reported pain score of surgical area preoperatively on a scale of 0-10	1 hour preoperatively
surgical site pain-2	reported pain score of surgical area preoperatively on a scale of 0-10 upon entry to PACU	1-2 hours postoperatively
surgical site pain-3	reported pain score of surgical area preoperatively on a scale of 0-10 on postoperative day 2	48 hours postoperatively
surgical site pain-4	reported pain score of surgical area preoperatively on a scale of 0-10 upon discontinuation of the bupivacaine infusion	72-120 hours postoperatively

Collaborators and Investigators

• Sponsor: Queen's University
• Investigators: Principal Investigator: Jessica Burjorjee, MD, FRCPC, Queen's University/Kingston General Hospital

Publications and helpful links

General Publications

• Burjorjee J, Phelan R, Hopman WM, Ho AM, Nanji S, Jalink D, Mizubuti GB. Plasma bupivacaine levels (total and free/unbound) during epidural infusion in liver resection patients: a prospective, observational study. Reg Anesth Pain Med. 2022 Aug 24:rapm-2022-103683. doi: 10.1136/rapm-2022-103683. Online ahead of print.

Study record dates

Study Major Dates

• Study Start (Actual): June 19, 2017
• Primary Completion (Actual): February 15, 2020
• Study Completion (Actual): February 15, 2020

Study Registration Dates

• First Submitted: May 5, 2017
• First Submitted That Met QC Criteria: May 8, 2017
• First Posted (Actual): May 9, 2017

Study Record Updates

• Last Update Posted (Actual): August 5, 2021
• Last Update Submitted That Met QC Criteria: July 29, 2021
• Last Verified: July 1, 2021

More Information

Terms related to this study

• Keywords: bupivacaine; Drug-Related Side Effects and Adverse Reactions; blood chemical analysis; local anesthetic toxicity
• Other Study ID Numbers: ANAE-300-16

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No