Reply: The Analgesic Effects of Liposomal Bupivacaine versus Bupivacaine Hydrochloride Administered as a Transversus Abdominis Plane Block after Abdominally Based Autologous Microvascular Breast Reconstruction: A Prospective, Single-Blind, Randomized, Controlled Trial (2020)

Sir: We thank Knackstedt et al. for their letter regarding our article,1 and share the common goal of optimizing postoperative analgesia for patients undergoing autologous breast reconstruction. Certainly, clinical practices must be driven by high-quality evidence. Our study is not the first published randomized controlled trial to compare the efficacy of liposomal bupivacaine and bupivacaine hydrochloride used in transversus abdominis plane blocks in patients undergoing autologous breast reconstruction. However, it was the first to do so in the context of an enhanced recovery after surgery protocol. To our knowledge, other trials used liposomal bupivacaine as part of a multitude of interventions included in their enhanced recovery after surgery protocols,2–4 or as part of an evolving postoperative analgesia protocol.5 In our study, preoperative, intraoperative, and postoperative management was identical for both patient groups with the sole exception of the local anesthetic agent used as single injections in intraoperative transversus abdominis plane blocks. Therefore, it represents a head-to-head comparison of liposomal bupivacaine versus bupivacaine hydrochloride. Gatherwright et al. do not specify their preoperative, intraoperative, or postoperative management protocol in their article and therefore it is difficult to determine whether liposomal bupivacaine was used as part of a larger enhanced recovery after surgery protocol.6 The inclusion of a heterogeneous group of patients undergoing unilateral or bilateral reconstruction does not by itself confound the efficacy of liposomal bupivacaine. The very design of a randomized controlled trial minimizes selection bias such as this one. In our study, there were no statistically significant differences between the liposomal bupivacaine and bupivacaine hydrochloride groups with respect to laterality and timing of reconstruction. Despite our randomized controlled trial design, there was a statistically significant difference in the proportion of patients with occasional preoperative opioid use. Daily opioid users were not enrolled. A post hoc analysis revealed that occasional opioid users actually had less total perioperative opioid consumption than the rest of the study cohort (312 mg versus 323 mg), but this was not statistically significant. This supported our conclusion that occasional preoperative opioid use did not confound our results. Average total perioperative opioid consumption in our trial was 283 mg for the liposomal bupivacaine group and 300 mg for the bupivacaine hydrochloride group. This is indeed significantly higher than the 40.9 and 79.9 mg reported by Gatherwright et al.6 However, it is important to note that much of this was perioperative. Our median postoperative opioid use was 139 and 165 mg, respectively. Rather than restricting our study to a limited patient population, we included bilateral procedures with more pain to maximize the potential for liposomal bupivacaine to show an improvement. We consider the paravertebral block an important part of our enhanced recovery after surgery protocol. Our previous research found that the block significantly reduces opioid requirements, 24-hour pain scores, and length of hospital stay.7 Bilateral paravertebral blocks can require 150 mg of 0.5% bupivacaine. To avoid local anesthetic toxicity, we do not add additional bupivacaine to the liposomal bupivacaine for the transversus abdominis plane block. Prior studies in both breast and nonbreast surgical procedures suggest that liposomal bupivacaine diluted with saline has early analgesic efficacy, as measured in pain scores or opioid consumption at 12 and 24 hours.8,9 With respect to sample size, we calculated that 52 patients in each group would be needed to achieve 80 power to detect a 20-mg difference in total opioid consumption with a significance level of alpha = 0.05. However, an interim analysis revealed that the difference in opioid consumption between groups was so small that 1337 patients per group would be needed to achieve 80 percent power to detect that difference (futility index, 0.97). Therefore, enrollment was terminated for futility at 22 patients per group. Although this is substantially larger than Gatherwright et al.’s eight patients per group, our Consolidated Standards of Reporting Trial–compliant study can be considered a pilot study based on number of patients. Larger studies in diverse patient populations are required to determine whether liposomal bupivacaine has any clinically significant benefits over plain bupivacaine in a transversus abdominis plane block in the setting of a robust enhanced recovery after surgery protocol. In our patient population, it is unlikely. We appreciate Knackstedt et al.’s interest in our work and the opportunity to further discuss this very important topic. Effective perioperative analgesia protocols speed patient recovery, reduce length of stay, and increase patient satisfaction. Although the evidence for the superiority of liposomal bupivacaine over placebo is rather robust, the same cannot yet be said for liposomal bupivacaine versus bupivacaine hydrochloride.8,9 We look forward to following the data from other institutions to help determine the best evidence-based practices for the autologous breast reconstruction patient. DISCLOSURE None of the authors has any relevant financial disclosures to report.