Bupivacaine Levels in Liver Resection Patients
Condition: Hepatectomy; Analgesia, Epidural
Study type: Observational

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.
    

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.
      
Biospecimen description: 
      Diagnostic 4 ml blood samples will be drawn from 20 liver resection patients sited with an
      epidural catheter for 3-5 days of bupivacaine infusion to manage their postoperative pain.
      Blood will be drawn by phlebotomy with standard of care blood blood-work at 4 time points:
      preoperatively, upon entry to the post-anesthesia care unit, 2 days postoperatively and then
      immediately before discontinuation bupivacaine infusion. Blood will be immediately
      centrifuged by the hospital laboratory and plasma divided into 2 aliquots to be stored at -70
      until all samples are collected- at which point they will be shipped to collaborators for
      analysis of AGP as well as bound and unbound bupivacaine.
    
Keywords: blood chemical analysis; bupivacaine; local anesthetic toxicity; Drug-Related Side Effects and Adverse Reactions