Title: Predicting safe re-dosing of bupivacaine and ropivacaine in truncal catheters

Authors: ^1,2Brittani Bungart MD PhD, ^1,2Lana Joudeh MD, ³Eric S. Schwenk MD, ⁴Michael Fettiplace MD PhD

Affiliations: ¹Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, MA, USA; ²Department of Anaesthesia, Harvard Medical School, Boston, MA, USA; ³Department of Anesthesiology and Perioperative Medicine, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA, USA; ⁴Department of Anesthesiology, University of Illinois Health, Chicago, IL, USA

Introduction: Bupivacaine and ropivacaine are frequently used for perioperative analgesia. While re-dosing of these medications is often needed for pain control, safe re-dosing recommendations are uncertain [1]. Pragmatic re-dosing parameters exist in the published literature via practitioner reports of intermittent bolus and breakthrough doses. Conversely, pharmacokinetic data exist to describe the excretion of bupivacaine and ropivacaine, providing formulas for safe delivery from an elimination perspective. To determine safe re-dosing of bupivacaine and ropivacaine for truncal catheters, we examined pharmacokinetic elimination rates and compared them to real-world re-dosing of bupivacaine and ropivacaine in truncal catheters.

Methods: The work was determined as non-human-subject-research and exempted from review by the Mass General Brigham institutional review board. For real-world re-dosing, we used a previously published dataset of paravertebral and transversus abdominis catheter infusions [2] that specifically utilized intermittent delivery or breakthrough bolus methods. For the pharmacokinetic elimination data, we identified manuscripts via a systematic search (on 5/28/2023) of Pubmed and Web of Science that examined metabolism of bupivacaine or ropivacaine and reported terminal elimination half-life in humans.  All abstracts and papers were screened, reviewed and data was extracted by two reviewers. Adult pharmacokinetic elimination rates of bupivacaine and ropivacaine, along with the number of patients, mean age, adjuvants, and delivery location, were extracted for all delivery methods and excluded if co-administered with drugs that affect P450 enzymes or were delivered with delayed-release vehicles. We modeled elimination pharmacokinetics based on average and minimum (i.e. slowest) elimination constants. Further, we compared the data to intermittent and breakthrough bolus infusion methods from the prior dataset. We compared group data using Mann-Whitney U-test (p<0.05 for significance). Curve fitting was performed with Prism 10 utilizing least squares regression without weighing for exponential plateau (Y= YM –{YM-Y0}*exp{-k*x}) and the extra-sum of squares F-test to compare the models.

Results: For the pharmacokinetic elimination data, we identified 45 publications with a total of 69 independent groups (Table 1). Consistent with prior results, intravenous delivery was associated with a faster elimination (Figure 1) compared to regional anesthetic delivery locations and were thus excluded from subsequent analysis.  Elimination constants were similar between ropivacaine and bupivacaine for both average elimination and minimum elimination (e.g. slowest elimination). Given the similar elimination rates, ropivacaine and bupivacaine were grouped for analysis with an average elimination constant of  k_Ave=0.18 hrs^-1 (95% confidence interval: 0.054 – 0.47 hrs^-1) and minimum elimination constant of k_Min=0.10 hrs^-1 (95% confidence interval: 0.039 – 0.23 hrs^-1) (Figure 2B).

     The pragmatic re-dosing data consisted of 62 infusions of intermittent bolus and breakthrough infusions of bupivacaine and ropivacaine into the paravertebral or transversus abdominis spaces (Table 2). Dosing characteristics are shown in Table 3 and were similar between groups, except for a longer intermittent bolus interval in bupivacaine catheters (median 8 hrs, range 3-12 hrs) compared to ropivacaine catheters (median 6 hrs, range 1-12 hrs, p=0.03). Re-dosing of the catheters over time with bupivacaine and ropivacaine fit a shared exponential plateau curve (extra-sum-of-squared F-test, F = 2.241(1,72), p=0.14) with the following equation: y_{IB_shared} (mg/kg)=3.0 mg/kg-(3.0 mg/kg*e^{-1∗time∗0.061})   (95% confidence interval: 0.051 – 0.071 hr^-1, R²=0.59), with weight-based dosing for a patient with 70 kg ideal body weight (Figure 2A).

Discussion: Herein, we analyzed safe re-dosing of ropivacaine and bupivacaine based respectively on real-world, truncal intermittent bolus and breakthrough infusions and pharmacokinetic elimination constants. Pragmatic re-dosing data fit to an exponential growth curve with an elimination constant of 0.061 hr^-1 and half-life of ~12 hrs. Assuming upper limits of 2.5-3.0 mg/kg in patients, re-dosing would equate to ~0.9 mg/kg at 6 hrs(~65 mg in 70 kg patient), 1.56 mg/kg at 12 hrs (~110 mg in 70 kg patient). This is below the mean slowest clearance curve that demonstrated an elimination constant of 0.1 hr^-1 and half-life of ~7 hrs with safe re-dosing of up to 1.35 mg/kg at 6 hrs (95 mg in 70 kg patient) and 2.1 mg/kg at 12 hrs (~150 mg in 70 kg patient). Mean clearance in the general population is even higher with an elimination constant of 0.18 hr^-1, half-life of 3.9 hrs, and re-dosing of ~2 mg/kg at 6 hrs(140 mg in a 70 kg patient) and a full dose at 12 hours. The lower limit data of 1 mg/kg at 6 hours comports with recent pharmacokinetic modeling that advises an upper limit of 1 mg/kg every six hours to avoid toxicity [3]. The upper limit data (full dose at 12 hours) comports with liberal dosing in healthy patients [4,5]. However, safe re-dosing can likely be accomplished with elimination constants of 0.061-0.1 hr^-1 reflecting doses of 0.92-1.35 mg/kg every 6 hrs. 

Summary of Findings: 

REAL WORLD PRACTICE (Figure 2B[IB shared fit])

Bupivacaine & ropivacaine truncal catheter re-dosing by ideal body weight with NO reported cases of toxicity:

ELIMINATION DATA (Figure 2B[Mean k_Min])

Bupivacaine & ropivacaine truncal catheter re-dosing by ideal body weight likely safe AT or BELOW: