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Comparative Methods to Predict Redosing of Bupivacaine and Ropivacaine in Truncal Catheters. BACKGROUND: Despite the frequent use of ropivacaine and bupivacaine, there is limited guidance on redosing of these medications after an initial bolus. Intermittent redosing is a clinical practice in the setting of nerve catheters, often utilizing large doses. Comparatively, theoretical elimination rates are available from pharmacokinetic studies, providing estimates on total body content of these drugs. The authors hypothesized that published redosing of bupivacaine and ropivacaine in clinical literature comported with safe elimination of the drugs based on pharmacokinetic studies. METHODS: Clinical redosing of bupivacaine and ropivacaine were identified from previously published articles that used intermittent bolus dosing into the transversus abdominis plane and paravertebral space. The dosing data were fit to an exponential curve using least squares regression and 1/Y 2 weighting with the equation: Y = Y M - (Y M - Y 0 ) * e -k * x , where YM is the maximal dose (175 mg for bupivacaine, 210 mg for ropivacaine), Y0 is the dose at time zero, k is the elimination constant, and x is time. Both minimal ( i.e. , slowest) and average pharmacokinetic elimination constants for ropivacaine and bupivacaine were identified in the published literature. Clinical redosing was compared with pharmacokinetic elimination. RESULTS: The maximal pharmacokinetic half-lives of bupivacaine and ropivacaine were 603 min (range, 154 to 2,970 min; N = 49) and 528 min (range, 204 to 3,276 min; N = 39), respectively. Clinically reported redosing of bupivacaine fit to an exponential curve with k bupi(clinical) = 0.077 h -1 , representing the 53.5th percentile of extracted pharmacokinetic minimal elimination constants. Clinically reported redosing of ropivacaine fit to a curve with k ropi(clinical) = 0.083 h -1 consistent with the 52nd percentile of minimal pharmacokinetic elimination constants. CONCLUSIONS: Clinically reported redosing of bupivacaine and ropivacaine in the published literature reflect the slowest pharmacokinetic elimination based on human studies. The combined data without evidence of toxicity permit the authors to make practical recommendations about safe redosing of these agents.

There is little rigorous testing about redosing schedules of local anesthetics in human patients, and decisions about redosing are often made empirically Local anesthetic systemic toxicity is a risk of local anesthetics, especially with repeat dosing, but the dosing range that minimizes the risk of local anesthetic systemic toxicity when delivered as a repeat bolus or infusion is uncertain The study compared two methods to estimate potentially safe redosing schedules, including (1) previously published redosing of bupivacaine and ropivacaine in truncal catheters in real patients who did not experience local anesthetic systemic toxicity and (2) terminal elimination data from previously published human pharmacokinetic studies on bupivacaine and ropivacaine Analysis of the two data sets identified a convergent outcome with the minimal elimination constants from pharmacokinetic studies predicting the clinical redosing in real patients Verification of these dosing schedules via measurement of local anesthetic concentrations is needed to confirm these calculated ranges for truncal catheters and other block types

Analysis of the two data sets identified a convergent outcome with the minimal elimination constants from pharmacokinetic studies predicting the clinical redosing in real patients Verification of these dosing schedules via measurement of local anesthetic concentrations is needed to confirm these calculated ranges for truncal catheters and other block types Along with opioids, cocaine-derived local anesthetics provide a mainstay of pain control for the more than 300 million surgeries worldwide each year.1 Of those local anesthetics, the highly lipophilic amide-linked bupivacaine and ropivacaine are utilized frequently for their potency and the long duration of analgesia they provide.2 Perioperative physicians frequently need to redose these local anesthetics to optimize pain control, either at an incision site or via continuous nerve catheters. While dosing recommendations exist for single-injection delivery of local anesthetics,3–6 there is limited guidance about redosing of local anesthetics. The ropivacaine package insert4 provides guidance on continuous delivery, specifically up to 28 mg/h, but does not detail redosing in the form of a bolus. Conversely, the bupivacaine package insert3 advises that a full dose can be delivered 3 h after the initial dose but does not provide any other guidance on redosing, including infusion rates. Short intervals between doses of long-acting local anesthetics can increase the risk of local anesthetic systemic toxicity with a recent pair of reviews identifying that total dose was the primary risk factor for local anesthetic systemic toxicity in continuous infusions.7,8 Even with the risk of toxicity, dosing frequently exceeds the package insert recommendations and Institutional Review Boards continue to approve these doses in “at risk” populations without monitoring for toxicity.9,10 Accordingly, redosing guidance is necessary for patient safety.

toxicity in continuous infusions.7,8 Even with the risk of toxicity, dosing frequently exceeds the package insert recommendations and Institutional Review Boards continue to approve these doses in “at risk” populations without monitoring for toxicity.9,10 Accordingly, redosing guidance is necessary for patient safety. In the absence of guidance, providers redose local anesthetics with intermittent bolus techniques based on the expected duration of action and frequently report these redosing paradigms in the literature. For theory-based redosing, pharmacokinetic data exist to describe the metabolism and excretion of bupivacaine and ropivacaine by the liver and kidneys, providing mathematical details about total drug removed from the body. We hypothesized that the clinically published redosing of truncal catheters would comport with theoretical “safe” redosing based on pharmacokinetic principles. We integrated the information to identify rational redosing paradigms for bupivacaine and ropivacaine.

There is little rigorous testing about redosing schedules of local anesthetics in human patients, and decisions about redosing are often made empirically Local anesthetic systemic toxicity is a risk of local anesthetics, especially with repeat dosing, but the dosing range that minimizes the risk of local anesthetic systemic toxicity when delivered as a repeat bolus or infusion is uncertain

The study compared two methods to estimate potentially safe redosing schedules, including (1) previously published redosing of bupivacaine and ropivacaine in truncal catheters in real patients who did not experience local anesthetic systemic toxicity and (2) terminal elimination data from previously published human pharmacokinetic studies on bupivacaine and ropivacaine Analysis of the two data sets identified a convergent outcome with the minimal elimination constants from pharmacokinetic studies predicting the clinical redosing in real patients Verification of these dosing schedules via measurement of local anesthetic concentrations is needed to confirm these calculated ranges for truncal catheters and other block types

We conducted a proof-of-principle study to assess whether the clinically reported redosing of bupivacaine and ropivacaine in paravertebral and transversus abdominis plane catheters comports with safe ranges based on pharmacokinetic elimination constants of these drugs. The project was determined as nonhuman research by the Mass General Brigham (Boston, Massachusetts) Institutional Review Board.

rted redosing of bupivacaine and ropivacaine in paravertebral and transversus abdominis plane catheters comports with safe ranges based on pharmacokinetic elimination constants of these drugs. The project was determined as nonhuman research by the Mass General Brigham (Boston, Massachusetts) Institutional Review Board. The “clinically reported” dosing data are an extension of a previous dataset of peripheral nerve catheters used in paravertebral and transversus abdominis plane blocks,7,8 chosen because of an absence of cases of local anesthetic systemic toxicity in the intermittent bolus group. We chose the paravertebral and transversus abdominis blocks because they are frequently administered as continuous local anesthetic infusions11,12 and are accompanied by large volumes and thus large total doses of local anesthetic to provide wide dermatomal coverage. This contrasts epidurals, for which practice has transitioned toward lower doses over the past 30 yr.13 Full details are described in the previous articles.7,8 In brief, we identified studies that described catheters placed into the transversus abdominis plane or paravertebral space in humans and dosed with either bupivacaine or ropivacaine for more than 24 h. We excluded studies that used other local anesthetics in the infusion, epidural catheters, catheters used for less than 24 h, and catheters explicitly placed in an alternative space (e.g., quadratus lumborum or erector spinae plane); articles with unobtainable doses, animal models, and liposomal bupivacaine; reviews; and conference abstracts.

used other local anesthetics in the infusion, epidural catheters, catheters used for less than 24 h, and catheters explicitly placed in an alternative space (e.g., quadratus lumborum or erector spinae plane); articles with unobtainable doses, animal models, and liposomal bupivacaine; reviews; and conference abstracts. Herein, we analyzed studies from the previous review of adult patients7 that utilized intermittent bolus methods (not solely continuous infusion) and/or breakthrough dosing to characterize the doses and intervals typically used in the literature. We excluded studies without explicit intervals between doses. In addition, we performed an updated literature search for studies published since our last review (2021 to 2024). For data analysis, the median dose from individual studies was prioritized as the measure of central tendency and mean was used if the median was unavailable. If the dosing varied over time, the dosing regimen for the first 24 h was utilized. For reported weight-based dosing, an ideal body weight of 70 kg was used to calculate a dose (seven bupivacaine studies and one 1 ropivacaine study). The data were analyzed and plotted in Prism 9.0 (GraphPad, USA). Constraints were set as Y0 = 0 mg, Ymax-ropi = 210 mg, Ymax-bupi = 175 mg, and k > 0. The package insert for bupivacaine3 recommends upper limit dosing of 175 mg without epinephrine, while guidelines,14 expert opinion,15 and textbooks16 advise weight-based dosing of 2.5 mg/kg without epinephrine. In contrast, the ropivacaine package insert4 recommends doses of up to 200 mg for field blocks,4 while textbooks5,16–18 and expert opinion19 advise up to 3.0 mg/kg without epinephrine. Given these differences, we chose 175 mg as the upper limit for bupivacaine to comport with 2.5 mg/kg in a 70-kg patient and 210 mg as the upper limit for ropivacaine to comport with 3.0 mg/kg in a 70-kg patient. The individual and shared curve fits, along with the 95% confidence and prediction intervals of the data were fit with the following equation: Y = YM – (YM – Y0) * e–k*x, where YM is the maximal dose (Ymax-ropi and Ymax-bupi), Y0 is the dose at time zero, k is the elimination constant, and x is time.

n a 70-kg patient. The individual and shared curve fits, along with the 95% confidence and prediction intervals of the data were fit with the following equation: Y = YM – (YM – Y0) * e–k*x, where YM is the maximal dose (Ymax-ropi and Ymax-bupi), Y0 is the dose at time zero, k is the elimination constant, and x is time. We used a single-phase elimination equation because bupivacaine and ropivacaine are primarily excreted after enzymatic metabolism in the liver, which is the major variable in terminal elimination due to the high binding percentage in the serum and the low extraction ratio of bupivacaine and ropivacaine.20 We conducted a sensitivity analysis comparing paravertebral to transversus abdominis plane dosing given the consideration that these spaces might be dosed differently by practitioners.

in terminal elimination due to the high binding percentage in the serum and the low extraction ratio of bupivacaine and ropivacaine.20 We conducted a sensitivity analysis comparing paravertebral to transversus abdominis plane dosing given the consideration that these spaces might be dosed differently by practitioners. For pharmacokinetic analysis, we evaluated the terminal elimination (i.e., elimination of the drug from the body by liver and kidneys) of both ropivacaine and bupivacaine with an assumption that maintaining total body local anesthetic content under a desired dose, which was 3.0 mg/kg for ropivacaine and 2.5 mg/kg for bupivacaine, should provide a safe upper limit of dosing. We identified articles from PubMed, Web of Science, and Google Scholar using the following search strategy: (bupivacaine OR ropivacaine) AND (“systemic pharmacokinetic” OR “pharmacokinetic parameters” OR “elimination half-life” OR “terminal half-life”) AND (patients OR volunteer OR volunteers OR human OR women OR men). We identified studies that examined metabolism of bupivacaine and/or ropivacaine and reported terminal half-life of excretion (or associated rate constant), including all routes of delivery (intravenous, subcuticular, intramuscular, peripheral nerve blocks, epidural, intrathecal, among others). Two reviewers (M.R.F. and B.B.) screened articles and extracted data. Extracted values included patient demographics, local anesthetic delivery method, adjuvants, sample collection method, and terminal elimination rates, including mean, maximum, and SD. Pediatric pharmacokinetic articles were identified but not included in the analysis.

.F. and B.B.) screened articles and extracted data. Extracted values included patient demographics, local anesthetic delivery method, adjuvants, sample collection method, and terminal elimination rates, including mean, maximum, and SD. Pediatric pharmacokinetic articles were identified but not included in the analysis. To determine theoretical safe dosing, we modeled pharmacokinetics based on the average terminal elimination half-life, reported as the mean or median. We also modeled dosing based on the maximum terminal elimination half-life or slowest elimination rate to account for slow processers of local anesthetic. If the maximum terminal elimination rate was not reported, we calculated the 97.5th percentile using NORMINV function in Excel (Microsoft, USA) using the mean and SD as inputs. Elimination half-lives were converted to the elimination constant by the equation ke=ln(2)t1/2. We plotted the average and upper-limit terminal elimination constants, along with the 95% CI of the data using the same single-order exponential elimination equation described in the clinically reported dosing section. We conducted a sensitivity analysis by removing all pharmacokinetic data that involved local anesthetic adjuvants (i.e., epinephrine, hyaluronidase, sufentanil, glucose, liposomes) or metabolism modifiers in intravenous studies (i.e., fluvoxamine, ketoconazole, erythromycin, rifampin, clarithromycin, itraconazole, ciprofloxacin, lipid emulsion), but we included data from pregnant patients and those with decreased creatinine clearance.

., epinephrine, hyaluronidase, sufentanil, glucose, liposomes) or metabolism modifiers in intravenous studies (i.e., fluvoxamine, ketoconazole, erythromycin, rifampin, clarithromycin, itraconazole, ciprofloxacin, lipid emulsion), but we included data from pregnant patients and those with decreased creatinine clearance. Data were analyzed in Prism 9.0 (GraphPad). Redosing data from clinically reported catheters were fit to exponential plateau curves as already described. Curve fitting within Prism utilized an exponential plateau model with least squares regression. To account for increased variability of dosing at longer time intervals, we compared no weighting along with weighting of 1/Y and 1/Y2 with minimization of Akaike information criterion while maintaining normality of residuals as determined by the D’Agostino-Pearson omnibus test. If residuals were nonnormal, we recalculated the fit after identification/elimination of outliers with Q = 1%. Clinically reported dosing is presented as medians and ranges, whereas curve fit estimates are presented as means and 95% CIs. CIs and prediction intervals were calculated within Prism using asymmetric profile likelihood calculation. Pharmacokinetic elimination data were evaluated for normality with Shapiro-Wilk tests, and nonnormal distributions were presented as medians and interquartile ranges. Paravertebral and transversus abdominis dosing was compared using the extra-sum-of-squares F test.

The “clinically reported” dosing data are an extension of a previous dataset of peripheral nerve catheters used in paravertebral and transversus abdominis plane blocks,7,8 chosen because of an absence of cases of local anesthetic systemic toxicity in the intermittent bolus group. We chose the paravertebral and transversus abdominis blocks because they are frequently administered as continuous local anesthetic infusions11,12 and are accompanied by large volumes and thus large total doses of local anesthetic to provide wide dermatomal coverage. This contrasts epidurals, for which practice has transitioned toward lower doses over the past 30 yr.13 Full details are described in the previous articles.7,8 In brief, we identified studies that described catheters placed into the transversus abdominis plane or paravertebral space in humans and dosed with either bupivacaine or ropivacaine for more than 24 h. We excluded studies that used other local anesthetics in the infusion, epidural catheters, catheters used for less than 24 h, and catheters explicitly placed in an alternative space (e.g., quadratus lumborum or erector spinae plane); articles with unobtainable doses, animal models, and liposomal bupivacaine; reviews; and conference abstracts.

For pharmacokinetic analysis, we evaluated the terminal elimination (i.e., elimination of the drug from the body by liver and kidneys) of both ropivacaine and bupivacaine with an assumption that maintaining total body local anesthetic content under a desired dose, which was 3.0 mg/kg for ropivacaine and 2.5 mg/kg for bupivacaine, should provide a safe upper limit of dosing. We identified articles from PubMed, Web of Science, and Google Scholar using the following search strategy: (bupivacaine OR ropivacaine) AND (“systemic pharmacokinetic” OR “pharmacokinetic parameters” OR “elimination half-life” OR “terminal half-life”) AND (patients OR volunteer OR volunteers OR human OR women OR men). We identified studies that examined metabolism of bupivacaine and/or ropivacaine and reported terminal half-life of excretion (or associated rate constant), including all routes of delivery (intravenous, subcuticular, intramuscular, peripheral nerve blocks, epidural, intrathecal, among others). Two reviewers (M.R.F. and B.B.) screened articles and extracted data. Extracted values included patient demographics, local anesthetic delivery method, adjuvants, sample collection method, and terminal elimination rates, including mean, maximum, and SD. Pediatric pharmacokinetic articles were identified but not included in the analysis.

Data were analyzed in Prism 9.0 (GraphPad). Redosing data from clinically reported catheters were fit to exponential plateau curves as already described. Curve fitting within Prism utilized an exponential plateau model with least squares regression. To account for increased variability of dosing at longer time intervals, we compared no weighting along with weighting of 1/Y and 1/Y2 with minimization of Akaike information criterion while maintaining normality of residuals as determined by the D’Agostino-Pearson omnibus test. If residuals were nonnormal, we recalculated the fit after identification/elimination of outliers with Q = 1%. Clinically reported dosing is presented as medians and ranges, whereas curve fit estimates are presented as means and 95% CIs. CIs and prediction intervals were calculated within Prism using asymmetric profile likelihood calculation. Pharmacokinetic elimination data were evaluated for normality with Shapiro-Wilk tests, and nonnormal distributions were presented as medians and interquartile ranges. Paravertebral and transversus abdominis dosing was compared using the extra-sum-of-squares F test.

We identified 68 articles with either intermittent bolus or breakthrough dosing of transversus abdominis plane or paravertebral catheters with a total of 74 bolus methods (supplemental tables S1, https://links.lww.com/ALN/D865, and S2, https://links.lww.com/ALN/D866). This included 6 breakthrough methods and 22 intermittent bolus methods for bupivacaine, along with 28 breakthrough methods, 16 intermittent bolus methods, and 2 mixed breakthrough/intermittent methods for ropivacaine. The median loading bolus was 75 mg (range, 30 to 210 mg) for ropivacaine and 75 mg (range, 25 to 150 mg) for bupivacaine. Four articles were excluded from the initial bolus calculation because of missing initial bolus data or administration of local anesthetics other than bupivacaine or ropivacaine in the initial bolus (i.e,. mepivacaine or lidocaine initial dose with ropivacaine redose).

e and 75 mg (range, 25 to 150 mg) for bupivacaine. Four articles were excluded from the initial bolus calculation because of missing initial bolus data or administration of local anesthetics other than bupivacaine or ropivacaine in the initial bolus (i.e,. mepivacaine or lidocaine initial dose with ropivacaine redose). Redosing for bupivacaine after the initial bolus (supplemental table S1, https://links.lww.com/ALN/D865) varied from 2.5 mg every 10 min at the low end, delivered as a patient-controlled dose,21 to 150 mg every 12 h delivered as an intermittent bolus.22 Redosing of bupivacaine fit best using 1/Y2 weighting (Akaike information criterion = –41.69) compared to 1/Y weight (Akaike information criterion = 74.44) or no weighting (Akaike information criterion = 194) with the following exponential curve: Ybupi (mg) = 175 mg – 175 * e(−1*time * k), kbupi = 0.077 h−1 (95% CI, 0.072 to 0.15; R2 = 0.79; D’Agostino–Pearson omnibus = 5.2; P = 0.07; fig. 1A). Using this equation, we calculated the clinically reported redose for bupivacaine in table 1. Sensitivity analysis confirmed no difference between paravertebral and transversus abdominis plane dosing (extra sum of F tests = 0.80(1,28); P = 0.38). Redosing of ropivacaine following the initial bolus varied from 10 mg every 15 min as a breakthrough dose23,24 up to 210 mg every 12 h administered as a redose.25 Redosing of ropivacaine fit best using 1/Y2 weighting (Akaike information criterion = –51.48) compared to 1/Y weight (Akaike information criterion = 104.3) or no weighting (Akaike information criterion = 292) with the following curve: Yropi (mg) = 210 mg – 210 * e(–1*time*k), kropi = 0.083 h–1 (95% CI, 0.068 to 0.098; R2 = 0.45; D’Agostino omnibus = 10.47; P = 0.0053.) Since the residuals were nonnormal, we recalculated after excluding four outliers.23,24,26,27 with the subsequent fit of Yropi (mg) = 210 mg – 210 * e(–1*time*k), kropi = 0.071 h–1 (95% CI, 0.06 to 0.0816; R2 = 0.68; Akaike information criterion = –65.29, D’Agostino omnibus = 2.1; P = 0.35; fig. 1B). Using this equation, we calculated the clinically reported redose for ropivacaine in table 1. Sensitivity analysis confirmed no difference between paravertebral and transversus abdominis plane dosing (extra sum of F tests = 3.4(1,41); P = 0.07). Of note, none of the included articles utilizing intermittent bolus techniques reported any patients experiencing signs or symptoms of local anesthetic systemic toxicity.

nsitivity analysis confirmed no difference between paravertebral and transversus abdominis plane dosing (extra sum of F tests = 3.4(1,41); P = 0.07). Of note, none of the included articles utilizing intermittent bolus techniques reported any patients experiencing signs or symptoms of local anesthetic systemic toxicity. Clinically Reported and Pharmacokinetically Computed Redose Bold values denote redosing at 6-h intervals. Intermittent bolus and breakthrough redosing of bupivacaine and ropivacaine in clinically reported truncal catheters. (A) Repeat bolus dose of bupivacaine with fit curve and 95% CI: Ybupi (mg) = 175 mg – 175 * e(−1*time * k); kbupi = 0.077 h−1 (95% CI, 0.072 to 0.15; R2 = 0.79; Akaike information criterion = −41.69; D’Agostino–Pearson omnibus = 5.2; P = 0.07). (B) Repeat bolus doses of ropivacaine with fit curve and 95% CI: Yropi (mg) = 210 mg – 210 * e(−1*time*k), kropi = 0.071 h−1 (95% CI, 0.06 to 0.0816; R2 = 0.68; Akaike information criterion = −65.29; D’Agostino omnibus = 2.1; P = 0.35).

Akaike information criterion = −41.69; D’Agostino–Pearson omnibus = 5.2; P = 0.07). (B) Repeat bolus doses of ropivacaine with fit curve and 95% CI: Yropi (mg) = 210 mg – 210 * e(−1*time*k), kropi = 0.071 h−1 (95% CI, 0.06 to 0.0816; R2 = 0.68; Akaike information criterion = −65.29; D’Agostino omnibus = 2.1; P = 0.35). Our literature query identified 39 articles with 55 distinct groups with terminal elimination half-lives for bupivacaine (supplemental tables S3, https://links.lww.com/ALN/D867, and S4, https://links.lww.com/ALN/D868). In comparison, we identified 34 publications with 69 distinct groups with terminal elimination half-lives for ropivacaine (supplemental tables S5, https://links.lww.com/ALN/D869, and S6, https://links.lww.com/ALN/D870). Intravenous delivery produced more rapid elimination in adult populations for both ropivacaine and bupivacaine (table 1) based on median (fig. 2A) and maximal half-lives (fig. 2B). Sensitivity analysis with adjuvants removed did not meaningfully change median half-lives or inter quartile ranges (supplemental fig. 1, https://links.lww.com/ALN/D871).

more rapid elimination in adult populations for both ropivacaine and bupivacaine (table 1) based on median (fig. 2A) and maximal half-lives (fig. 2B). Sensitivity analysis with adjuvants removed did not meaningfully change median half-lives or inter quartile ranges (supplemental fig. 1, https://links.lww.com/ALN/D871). Comparison of terminal elimination half-life by drug, location and age group. (A) Average elimination half-life for intravenous (IV) ropivacaine (Ropi; median = 148 min, range = 84 to 714, n = 29 groups), intravenous bupivacaine (Bupi; median = 172 min, range = 115 to 227, n = 5 groups), peripheral/neuraxial ropivacaine (median = 318 min, range = 122 to 870, n = 40 groups), and peripheral/neuraxial bupivacaine (median = 341 min, range = 80 to 890, n = 50 groups). (B) Maximal elimination half-life for intravenous ropivacaine (median = 251 min, range = 119 to 1,436, n = 29 groups), intravenous bupivacaine (median = 351 min, range = 142 to 427, n = 5 groups), peripheral/neuraxial ropivacaine (median = 528 min, range = 204 to 3,276, n = 39 groups), and peripheral/neuraxial bupivacaine (median = 603 min, range = 154 to 2,970, n = 49 groups).

e (median = 251 min, range = 119 to 1,436, n = 29 groups), intravenous bupivacaine (median = 351 min, range = 142 to 427, n = 5 groups), peripheral/neuraxial ropivacaine (median = 528 min, range = 204 to 3,276, n = 39 groups), and peripheral/neuraxial bupivacaine (median = 603 min, range = 154 to 2,970, n = 49 groups). Using the elimination half-lives, we constructed plots for total elimination of bupivacaine (fig. 3, A and B) and ropivacaine (fig. 3, C and D) and projected the anticipated redosing of these drugs based on pharmacokinetic elimination (table 1). We directly compared the clinically published redosing model with the average and slowest terminal elimination data (table 1, fig. 4). For bupivacaine, the median of the slowest elimination was k = 0.069 (t1/2 = 603 min; table 2). The clinically published redosing data for bupivacaine fit to the 53.5th percentile of the slowest elimination (95% CI, 52nd percentile to 89th percentile) with overlapping curves in figure 4A. The 75th percentile of the average elimination encompassed most clinical redosing and reflected the 95% prediction interval of clinically reported redosing (table 1).7 For ropivacaine, we observed the same relationship with the median of slowest elimination (k = 0.08, t1/2 = 528 min; table 2). The clinically published redosing data for ropivacaine with outliers included fit to the 52nd percentile of the slowest elimination (95% CI, 28th percentile to 62nd percentile), whereas the clinically published redosing with outliers excluded fit to the 40th percentile of the slowest elimination (95% CI, 31st percentile to 52nd percentile; fig. 4B). The ropivacaine average terminal elimination (k = 0.128, t1/2 = 318 min) also fell within the 95% prediction interval for clinically reported dosing (table 1).

linically published redosing with outliers excluded fit to the 40th percentile of the slowest elimination (95% CI, 31st percentile to 52nd percentile; fig. 4B). The ropivacaine average terminal elimination (k = 0.128, t1/2 = 318 min) also fell within the 95% prediction interval for clinically reported dosing (table 1). Elimination Half-life and Elimination Time Constants Values are expressed as median [interquartile range]. IV, intravenous. Removal of bupivacaine and ropivacaine for mean and slowest elimination rates. (A) Bupivacaine elimination assuming a 2.5-mg/kg bolus based on average terminal elimination rates with 5%, 25%, 50%, 75%, and 95% curves. (B) Bupivacaine elimination assuming a 2.5-mg/kg bolus based on the slowest terminal elimination rates with 5%, 25%, 50%, 75%, and 95% curves. (C) Same as (A) for ropivacaine and assuming a 3.0-mg/kg bolus. (D) Same as (B) for ropivacaine and assuming a 3.0-mg/kg bolus.

ion rates with 5%, 25%, 50%, 75%, and 95% curves. (B) Bupivacaine elimination assuming a 2.5-mg/kg bolus based on the slowest terminal elimination rates with 5%, 25%, 50%, 75%, and 95% curves. (C) Same as (A) for ropivacaine and assuming a 3.0-mg/kg bolus. (D) Same as (B) for ropivacaine and assuming a 3.0-mg/kg bolus. Redosing of ropivacaine and bupivacaine based on clinically reported infusions and pharmacokinetic (PK) elimination. (A) Combined clinically reported intermittent bolus and breakthrough redosing of bupivacaine in transversus abdominis and paravertebral catheters (blue curves) in published literature with exponential fit curve with plateau of 2.5 mg/kg (or 175 mg in 70-kg patient) and k = 0.077 h−1 along with 95% prediction interval; overlay of pharmacokinetic elimination of 2.5 mg/kg (or 175 mg in 70-kg patient) assuming first order kinetics based on median elimination constant k = 0.12 h−1 (interquartile range = 0.08 to 0.18) along with minimum elimination k = 0.069 h−1 (interquartile range = 0.05 to 0.11). (B) Combined clinically reported intermittent bolus and breakthrough redosing of ropivacaine in transversus abdominis and paravertebral catheters (pink curves) in published literature with fit curve exponential fit curve with plateau of 3.0 mg/kg (or 210 mg in 70-kg patient) and k = 0.071 h−1 along with 95% prediction interval; overlay of pharmacokinetic elimination of 3.0 mg/kg (or 210 mg in a 70-kg patient) based on median elimination constant k = 0.13 h−1 (interquartile range = 0.1 to 0.20) along with minimum clearance k = 0.08 h−1 (interquartile range = 0.046 to 0.145).

70-kg patient) and k = 0.071 h−1 along with 95% prediction interval; overlay of pharmacokinetic elimination of 3.0 mg/kg (or 210 mg in a 70-kg patient) based on median elimination constant k = 0.13 h−1 (interquartile range = 0.1 to 0.20) along with minimum clearance k = 0.08 h−1 (interquartile range = 0.046 to 0.145). Given that clinically published redosing reflected the minimal pharmacokinetic elimination constant, it is likely that safe and rationale redosing can be predicted based on these parameters (table 1). This is supported by the observation that no cases of catheter-based toxicity were observed in these subgroups in our recent analysis of the literature.7 Conversely, doses above the 75th percentile (upper limit of pharmacokinetic interquartile range) of the median average elimination and outside the 95% prediction interval of clinically reported dosing are potential risk factors for toxicity; this would include hourly bolus doses of more than 0.4 mg/kg bupivacaine or 0.5 mg/kg ropivacaine. Based on the low rates of obesity in many of the included studies we anticipate this reflects ideal-body-weight dosing but may more accurately be reflected by lean-body-weight dosing.

potential risk factors for toxicity; this would include hourly bolus doses of more than 0.4 mg/kg bupivacaine or 0.5 mg/kg ropivacaine. Based on the low rates of obesity in many of the included studies we anticipate this reflects ideal-body-weight dosing but may more accurately be reflected by lean-body-weight dosing. We utilized the pharmacokinetic elimination curves to make predictions about continuous infusions assuming continuous elimination over short periods of time (e.g., less than 5 min; table 3) and extrapolated to rational 24-h limits. By integrating under the fit curve for clinically published redosing, or by integrating under the pharmacokinetic elimination curve, we can predict how much is processed continuously and make assertions about continuous infusion limits. The clinically reported data integrate (mathematically) to infusion rates of 12 mg/h for bupivacaine and 15 mg/h for ropivacaine for a 70 kg patient for paravertebral or transversus abdominis plane infusions. These are consistent with published infusion rates (anticipated immediately after a full bolus dose of 3.0 mg/kg ropivacaine or 2.5 mg/kg bupivacaine).7,8 The infusion rate dosing based on minimal pharmacokinetic elimination constant integrates to reflect conservative dosing (in a 70-kg patient, interquartile range of 10 to 26 mg/h of ropivacaine and 9 to 19 mg/h of bupivacaine). These integrated parameters based on population pharmacokinetics are identical to practice patterns for continuous infusions in patients treated with ropivacaine and bupivacaine in transversus abdominis plane and paravertebral blocks.7 The 75th percentile (upper limit of interquartile range) based on average elimination rate predict rates of up to 0.45 mg · kg–1 · h–1 for bupivacaine and 0.6 mg · kg–1 · h–1 for ropivacaine. These doses reflect thresholds of toxicity seen in truncal infusions in our previous review and provide pharmacokinetic validation that doses at or above these are toxic and necessitate justification and/or special monitoring.

rates of up to 0.45 mg · kg–1 · h–1 for bupivacaine and 0.6 mg · kg–1 · h–1 for ropivacaine. These doses reflect thresholds of toxicity seen in truncal infusions in our previous review and provide pharmacokinetic validation that doses at or above these are toxic and necessitate justification and/or special monitoring. Calculated Infusion Dosing Based on Clinical Reports and Pharmacokinetic Elimination Values are expressed as median [interquartile range]. The 24-h infusion-limit assumes starting immediately following a maximal bolus of 3.0 mg/kg for ropivacaine or 2.5 mg/kg for bupivacaine. IQR, interquartile range; PK, pharmacokinetic.

Our literature query identified 39 articles with 55 distinct groups with terminal elimination half-lives for bupivacaine (supplemental tables S3, https://links.lww.com/ALN/D867, and S4, https://links.lww.com/ALN/D868). In comparison, we identified 34 publications with 69 distinct groups with terminal elimination half-lives for ropivacaine (supplemental tables S5, https://links.lww.com/ALN/D869, and S6, https://links.lww.com/ALN/D870). Intravenous delivery produced more rapid elimination in adult populations for both ropivacaine and bupivacaine (table 1) based on median (fig. 2A) and maximal half-lives (fig. 2B). Sensitivity analysis with adjuvants removed did not meaningfully change median half-lives or inter quartile ranges (supplemental fig. 1, https://links.lww.com/ALN/D871).

We utilized the pharmacokinetic elimination curves to make predictions about continuous infusions assuming continuous elimination over short periods of time (e.g., less than 5 min; table 3) and extrapolated to rational 24-h limits. By integrating under the fit curve for clinically published redosing, or by integrating under the pharmacokinetic elimination curve, we can predict how much is processed continuously and make assertions about continuous infusion limits. The clinically reported data integrate (mathematically) to infusion rates of 12 mg/h for bupivacaine and 15 mg/h for ropivacaine for a 70 kg patient for paravertebral or transversus abdominis plane infusions. These are consistent with published infusion rates (anticipated immediately after a full bolus dose of 3.0 mg/kg ropivacaine or 2.5 mg/kg bupivacaine).7,8 The infusion rate dosing based on minimal pharmacokinetic elimination constant integrates to reflect conservative dosing (in a 70-kg patient, interquartile range of 10 to 26 mg/h of ropivacaine and 9 to 19 mg/h of bupivacaine). These integrated parameters based on population pharmacokinetics are identical to practice patterns for continuous infusions in patients treated with ropivacaine and bupivacaine in transversus abdominis plane and paravertebral blocks.7 The 75th percentile (upper limit of interquartile range) based on average elimination rate predict rates of up to 0.45 mg · kg–1 · h–1 for bupivacaine and 0.6 mg · kg–1 · h–1 for ropivacaine. These doses reflect thresholds of toxicity seen in truncal infusions in our previous review and provide pharmacokinetic validation that doses at or above these are toxic and necessitate justification and/or special monitoring.

In this study, we found that the published redosing strategies of bupivacaine and ropivacaine used by anesthesiologists in paravertebral and transversus abdominis plane catheters are generally safe based on pharmacokinetic elimination parameters. The clinically reported redosing fit to an exponential plateau with time constants that reflected the 50th percentile (or below) of the slowest pharmacokinetic elimination constants, indicating that currently employed doses fall well within the anticipated pharmacokinetic limits of safety. Confirming this safety was the fact that local anesthetic systemic toxicity events were not detected in the intermittent bolus groups of our preceding reviews.7,8 Some practitioners dosed beyond the average elimination constant as illustrated by a study25 of liver resection patients in whom total blood levels continued to rise, but unbound levels remained constant due to upregulation of α1-acid glycoprotein.

detected in the intermittent bolus groups of our preceding reviews.7,8 Some practitioners dosed beyond the average elimination constant as illustrated by a study25 of liver resection patients in whom total blood levels continued to rise, but unbound levels remained constant due to upregulation of α1-acid glycoprotein. The pharmacokinetic data identified an average elimination half-life for both bupivacaine and ropivacaine of approximately 5 to 6 h in peripheral/neuraxial delivery, whereas the slowest elimination half-life for both drugs was 8 to 10 h. Consistent with previous literature,28 cytochrome P-450 inhibitors, (fluvoxamine, erythromycin),29 end-stage liver disease,30 and uremia were the most obvious contributors to reduced elimination. Other risk factors such as cachexia, malnourished states, hypoalbuminemia, albumin-binding competitors, reduced cardiac output, acidosis, and metabolic disease were not systematically studied. Taking a safe dosing approach, practitioners can likely redose patients using minimum elimination rates (table 4, “Safe Redose”). A rational and safe recommendation is approximately 10 mg/h (in a 70-kg patient) or 0.15 mg · kg–1 · h–1 (based on ideal or lean body weight) over the first 6 h for both bupivacaine and ropivacaine. Some patients may tolerate higher doses, but practitioners will increase the risk of toxicity above the 75% inter-quartile range of the median clearance (table 4, “Danger Threshold”). The “safe” dosing reflects a recent pharmacokinetic study in erector spinae plane blocks31 that predicted weight-based redosing of ropivacaine up to 1.2 mg/kg every 6 h based on lean body weight or 0.9 mg/kg based on ideal body weight.32 Patients with previously identified risk factors will benefit from lower dosing and patients with liver disease potentially warrant monitoring of blood levels.

lane blocks31 that predicted weight-based redosing of ropivacaine up to 1.2 mg/kg every 6 h based on lean body weight or 0.9 mg/kg based on ideal body weight.32 Patients with previously identified risk factors will benefit from lower dosing and patients with liver disease potentially warrant monitoring of blood levels. Rational Redosing Recommendations The doses (in mg/kg) are based on ideal or lean body weight. The doses for a 70-kg patient are shown in parentheses (in mg). Values in bold denote redosing at 6-h intervals. These redosing limits assume no other delivery of local anesthetic aside from an initial bolus and rebolus. Dose based on median of slowest elimination constants. Dose based on upper quartile of average elimination constants. Comparatively, patients with no known risk factors and normal muscle mass undergoing low-risk procedures (e.g, noncardiac, vascular, thoracic, or hepatic) could tolerate higher doses (table 4, “Danger Threshold”) but with the tradeoff of increased risk of toxicity. Further studies are needed to confirm these recommendations because toxicity occurs on a spectrum and some patients may experience symptoms at lower-than-predicted plasma levels. High dosing rates should not be assumed for sick patients, as illustrated by a recent case of death in a 4-yr-old who received 0.39 mg · kg–1 · h–1 of ropivacaine for 4 days via an elastomeric infusion pump. This dose is consistent with the “average” ropivacaine elimination but obviously faster than should be expected in 50% of patients (by definition of average elimination).33

s illustrated by a recent case of death in a 4-yr-old who received 0.39 mg · kg–1 · h–1 of ropivacaine for 4 days via an elastomeric infusion pump. This dose is consistent with the “average” ropivacaine elimination but obviously faster than should be expected in 50% of patients (by definition of average elimination).33 In adult populations, precedent exists for redosing with large doses of ropivacaine and bupivacaine as detailed in table 4. In the clinically reported truncal-catheter data, we observed redosing of bupivacaine up to 10 mg every 30 min as needed34 or 100 mg every 4 h as needed.35 For ropivacaine, practitioners redosed up to 40 mg every hour as needed,27 20 mg every 30 min as needed,36 or 10 mg every 15 min as needed.23,24 However, all four of these dosing parameters were identified as outliers. At longer intervals, Ollier et al. dosed 210 mg every 12 h in a pharmacokinetic study that demonstrated no risk of toxicity in patients receiving liver resections.25 Higher doses are being studied in an ongoing clinical trial, randomizing patients to receive up to 42 mg/h including 1 ml/h of basal rate and 13 ml of 0.3% every hour for bilateral erector spinae plane catheters. However, the pharmacokinetic data herein would predict that this dose is dangerous in most patients with an ideal body weight less than 78 kg or with comorbidities. The same is true for previous randomized trials that infused up to 0.6 mg · kg–1 · h–1.9,10 Trials with doses this high likely require additional safety monitoring.

the pharmacokinetic data herein would predict that this dose is dangerous in most patients with an ideal body weight less than 78 kg or with comorbidities. The same is true for previous randomized trials that infused up to 0.6 mg · kg–1 · h–1.9,10 Trials with doses this high likely require additional safety monitoring. One major implication for these dosing approaches is the development of calculators for use in redoing of local anesthetics.37 Currently, a few algorithms are available for calculating upper-limit doses, but they have limitations, including lack of clarification about use of ideal or lean body weight. Consequently, these calculators may advise toxic doses if using actual body weight. Previous dose calculators37 consider only the initial bolus doses without accounting for the interval between the initial injection and subsequent injections. Based on the elimination data, an otherwise healthy patient with a high lean body weight (e.g., muscular 70- or 80-kg person) could safely receive 30 ml of 0.25% bupivacaine or ropivacaine (75 mg) as a local infiltration 4 h after receiving 175 mg of that same local anesthetic for sciatic and femoral nerve blocks at the beginning of surgery. However, this could become dangerous for a 50-kg person, for a patient with American Society of Anesthesiologists physical status III, or at a shorter interval (e.g., as local infiltration analgesia 1 h after blocks in a knee replacement at a high-turnover outpatient surgical center).38 The data herein also contradict the bupivacaine package insert,3 which recommends a full redose at 3 h. As a general rule, using the rule of lowest effective dose will provide the greatest margin of safety and prevent most local anesthetic systemic toxicity events.

This is a proof-of-concept study with associated limitations. We used a systematic search to identify articles for both the pharmacokinetic and clinically published dosing but may have missed some studies. There are no formalized systematic reviews on the clinical pharmacokinetics of bupivacaine or ropivacaine, and the field would likely benefit from these studies with a validated risk-of-bias tool. There are also no formalized systematic reviews or meta-analyses for dosing because it is an independent variable instead of an outcome and thus does not fit well into a population–intervention–comparator–outcome framework. For the pharmacokinetic data, we assessed elimination half-life without considering absorption but recognize that absorption can contribute to the elimination constant. This likely caused the differences between the observed data for intravenous and peripheral/neuraxial delivery. We conducted a sensitivity analysis without additives (i.e., epinephrine) and found no difference in curve fit. Additives like epinephrine may prolong absorption, decreasing peak concentrations, but these should not affect terminal elimination. In the clinically reported dosing, epinephrine was rarely used in redoses.39

e conducted a sensitivity analysis without additives (i.e., epinephrine) and found no difference in curve fit. Additives like epinephrine may prolong absorption, decreasing peak concentrations, but these should not affect terminal elimination. In the clinically reported dosing, epinephrine was rarely used in redoses.39 We used the median elimination constant to reflect the overall population and used the upper limit of half-life to reflect the slowest processing (and most at risk from toxicity by redosing), which may not account for all scenarios (particularly fast eliminators). However, this likely takes into account patients with underlying pathology that will put them at risk for local anesthetic systemic toxicity. Next, we assumed first-order excretion for ropivacaine40 and bupivacaine, which is largely correct, but elimination rates can change dramatically over the initial 24 h,41,42 so dosing recommendations may not apply over prolonged periods. Further, the data does not address the issue of multiple local anesthetic injection locations or different types of local anesthetic. Previous studies demonstrated that local anesthetics produce either additive43 or synergistic44 toxicity. We therefore recommend following additive limits as currently utilized in some dosing calculators.37 We did not take sample size into account, which may provide a skew to our results. Last, our results describe only what has been published, and clinical studies in the literature may not represent what is being done by average clinicians, so our results may not be generalizable to some clinicians and practices.

We conducted a proof-of principle study to assess redosing of bupivacaine and ropivacaine in truncal catheters. Consistent with our hypothesis, clinically reported redosing reflected the slowest elimination constants from pharmacokinetic studies, which likely represents safe dosing in most patients. Using these data, we provide rational dosing recommendations (tables 3 and 4) that comport with previous human studies.31 We also use the data to identify a threshold of danger for toxicity that comports with thresholds identified in earlier publications.7 As always, “lowest effective dose” is a practice that will improve patient safety, especially in the setting of known risk factors for local anesthetic systemic toxicity.45 Further investigation is needed to validate these doses in pragmatic pharmacokinetic trials. The field would also benefit from confirmation of these data in other block locations (e.g., erector spinae plane blocks, upper and lower extremity catheters) and with other local anesthetics (i.e., lidocaine). Supported by National Institutes of Health (Bethesda, Maryland) T32 training grant No. 5T32GM007592-42 and by departmental funding (to Dr. Fettiplace). Dr. Bungart is co-founder of Bitaic, Inc. (Melrose, Massachusetts), and is a co-founder, board member, and company officer of Stornamics, Inc (Melrose, Massachusetts). Dr. Schwenk contributes to UpToDate.com (Waltham, Massachusetts). The other authors declare no competing interests.

Dr. Bungart is co-founder of Bitaic, Inc. (Melrose, Massachusetts), and is a co-founder, board member, and company officer of Stornamics, Inc (Melrose, Massachusetts). Dr. Schwenk contributes to UpToDate.com (Waltham, Massachusetts). The other authors declare no competing interests.

Supplemental Table S1. Clinically reported bupivacaine redosing, https://links.lww.com/ALN/D865 Supplemental Table S2. Clinically reported ropivacaine redosing, https://links.lww.com/ALN/D866 Supplemental Table S3. Bupivacaine peripheral/neuraxial pharmacokinetic elimination, https://links.lww.com/ALN/D867 Supplemental Table S4. Bupivacaine intravenous pharmacokinetic elimination, https://links.lww.com/ALN/D868 Supplemental Table S5. Ropivacaine peripheral/neuraxial pharmacokinetic elimination, https://links.lww.com/ALN/D869 Supplemental Table S6. Ropivacaine intravenous pharmacokinetic elimination, https://links.lww.com/ALN/D870 Supplemental Figure S1. Elimination half-life without adjuvants, https://links.lww.com/ALN/D871