LAUSR

I appreciate the interest of Hoegberg et al. in our meta-analysis and am happy to address their concerns. With regard to the meta-analysis (e.g., forest and funnel plots), “we examined all experimental studies with survival effects (e.g., we excluded studies in which all animals lived or all animals died) and further included studies with ILE as the independent variable [1]”. Meta-analysis requires inclusion of studies that analyze the same experimental outcome (herein, survival). Other studies were not excluded arbitrarily but specifically because ILE was not an independent variable with controls, or because survival was not an intended metric of study. In particular, the Buckenmaier study tested “... the effects of simulated postmortem conditions (low temperature and time) and lipid emulsion use on preand postmortem serum ropivacaine concentrations [2]”. Contrary to my colleagues’ assertion, we included the mepivacaine study in the analysis (see our Table 1). However, we noted that it fell outside the bounds of the funnel plot, possibly owing to the use of a different local anesthetic (mepivacaine versus bupivacaine). Further, we addressed the remaining excluded studies in “Studies without a quantitative difference” section of the discussion. We made no explicit statement about pigs as a model for lipid resuscitation and did not address that question in our manuscript. However, swine suffer from a hypersensitivity reaction to ILE so their use as an experimental model for lipid resuscitation is questionable as the hypersensitivity may skew outcomes [3]. I agree with Hoegberg et al. that evidence supports ILE for bupivacaine toxicity, but they confound this statement by adding a comparison to vasopressors. Support for ILE in local anesthetic toxicity stems from frequent case reports, homogenous meta-analysis of animal data [1], mechanistic benefit in animal models [4,5], and mechanistic benefit in human randomized controlled trials [6,7] while support for vasopressors or bicarbonate stems from the dogma of symptomatic treatment. A claim of theoretical equipoise between ILE, vasopressors, and bicarbonate, as first-line agents, would require similar systematic review, meta-analysis, and mechanistic benefit for those agents. In the absence of such studies, the statement is not evidence-based. As we mentioned in the article, ILE arose as a therapy for local anesthetic systemic toxicity because standard resuscitation measures, vasopressors and epinephrine included, resulted in poor outcomes clinically [8] and experimentally [9]. To summarize, our meta-analysis supports the use of lipid emulsion as a treatment for bupivacaine toxicity in animal models (along with ventilation and hemodynamic support including chest compressions if needed). I appreciate my colleagues’ work to address the indications, efficacy, and optimal use of ILE as they are important questions. Advancing these topics will require careful reading and rigorous science. I look forward to the continued progress and discussion of these subjects within the community.