Clinical trial NCT03145805: Bupivacaine Levels in Liver Resection Patients
Official title: Blood Levels of Bupivacaine in Liver Resection Patients Sited With an Epidural Catheter for Postoperative Pain Control
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Hepatectomy
Analgesia, Epidural
Keywords: blood chemical analysis
bupivacaine
local anesthetic toxicity
Drug-Related Side Effects and Adverse Reactions
Lead sponsor: Queen's University
Sponsor class: OTHER
First posted: 2017-05-09
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
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.

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: bound bupivacaine levels-1
timeFrame: 1-2 hours following surgery
measure: bound bupivacaine levels-2
timeFrame: 48 hours following surgery
measure: bound bupivacaine levels-3
timeFrame: 72-120 hours following surgery
measure: unbound bupivacaine levels-4
timeFrame: 1-2 hours following surgery
measure: unbound bupivacaine levels-5
timeFrame: 48 hours following surgery
measure: unbound bupivacaine levels-6
timeFrame: 72-120 hours following surgery
measure: alpha-1-acid glycoprotein levels-(AGP)-1
timeFrame: 1 hour preoperatively
measure: alpha-1-acid glycoprotein levels-(AGP)-2
timeFrame: 1-2 hours postoperatively
measure: alpha-1-acid glycoprotein levels-(AGP)-3
timeFrame: 48 hours postoperatively
measure: alpha-1-acid glycoprotein levels-(AGP)-4
timeFrame: 72-120 hours postoperatively
Secondary outcomes:
measure: signs/symptoms of local anesthetic toxicity-1
timeFrame: 1 hour preoperatively
measure: signs/symptoms of local anesthetic toxicity-2
timeFrame: 1-2 hours postoperatively
measure: signs/symptoms of local anesthetic toxicity-3
timeFrame: 48 hours postoperatively
measure: signs/symptoms of local anesthetic toxicity-4
timeFrame: 72-120 hours postoperatively
measure: surgical site pain-1
timeFrame: 1 hour preoperatively
measure: surgical site pain-2
timeFrame: 1-2 hours postoperatively
measure: surgical site pain-3
timeFrame: 48 hours postoperatively
measure: surgical site pain-4
timeFrame: 72-120 hours postoperatively
Other outcomes:
Locations:
city: Kingston
country: Canada
facility: Kingston General Hospital
state: Ontario
Study officials:
affiliation: Queen's University/Kingston General Hospital
name: Jessica Burjorjee, MD, FRCPC
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.