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Published on: August 2, 2019
Resuscitation with lipid emulsion: dose-dependent recovery from cardiac pharmacotoxicity requires a cardiotonic
Michael R Fettiplace1, Belinda S Akpa, Richard Ripper
1From the Department of Anesthesiology, University of Illinois College of Medicine, Chicago, Illinois (M.R.F., R.R., and G.W.); Research and Development Service, Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois (M.R.F., R.R., I.R., and G.W.); University of Illinois College of Medicine, Chicago, Illinois (M.R.F. and B.Z.); Department of Chemical Engineering, University of Illinois at Chicago, Chicago, Illinois (B.S.A.); University of Illinois College of Medicine, Peoria, Illinois (J.L.); and Section of Pulmonary, Critical Care, Sleep, and Allergy Medicine, Department of Medicine, University of Illinois College of Medicine, Chicago, Illinois (I.R.).
Insights
Intravenous lipid emulsion accelerates recovery from bupivacaine toxicity in a dose-dependent manner. This effect is driven by a cardiotonic response, complementing lipid sequestration.
Area of Science:
- Anesthesiology
- Toxicology
- Pharmacology
Background:
- Debate exists regarding the mechanism of lipid resuscitation for local anesthetic toxicity.
- Alternative theories include hemodilution and sink-independent effects.
- This study investigates the dose-dependent response to intravenous lipid emulsion in bupivacaine toxicity.
Purpose of the Study:
- To test the dose-dependent response to intravenous lipid emulsion during reversal of bupivacaine-induced cardiovascular toxicity.
- To model the relative contributions of volume resuscitation, drug sequestration, and inotropy to the recovery response.
Main Methods:
- Rats received bupivacaine-induced cardiovascular toxicity and were randomized to receive 30% lipid emulsion, 20% lipid emulsion, saline, or no treatment.
- Cardiovascular metrics were monitored throughout the study.
- Recovery responses were compared to predictions from a pharmacokinetic-pharmacodynamic model.
Main Results:
- Lipid emulsion treatment resulted in faster recovery compared to saline or no treatment.
- 30% lipid emulsion showed the fastest hemodynamic recovery, followed by 20% lipid emulsion, saline, and no treatment.
- Increased arterial blood pressure was observed in lipid emulsion groups; heart rates remained depressed.
Conclusions:
- Intravenous lipid emulsion accelerates cardiovascular recovery from bupivacaine toxicity in a dose-dependent manner.
- The recovery is driven by a cardiotonic response that enhances the known sequestration effect.
- A combined model of volume, sequestration, and inotropy most accurately predicted in vivo results.
Background:
Recent publications have questioned the validity of the "lipid sink" theory of lipid resuscitation while others have identified sink-independent effects and posed alternative mechanisms such as hemodilution. To address these issues, the authors tested the dose-dependent response to intravenous lipid emulsion during reversal of bupivacaine-induced cardiovascular toxicity in vivo. Subsequently, the authors modeled the relative contribution of volume resuscitation, drug sequestration, inotropy and combined drug sequestration, and inotropy to this response with the use of an in silico model.
Methods:
Rats were surgically prepared to monitor cardiovascular metrics and deliver drugs. After catheterization and instrumentation, animals received a nonlethal dose of bupivacaine to produce transient cardiovascular toxicity, then were randomized to receive one of the four treatments: 30% intravenous lipid emulsion, 20% intravenous lipid emulsion, intravenous saline, or no treatment (n = 7 per condition; 28 total animals). Recovery responses were compared with the predictions of a pharmacokinetic-pharmacodynamic model parameterized using previously published laboratory data.
Results:
Rats treated with lipid emulsions recovered faster than did rats treated with saline or no treatment. Intravenous lipid emulsion of 30% elicited the fastest hemodynamic recovery followed in order by 20% intravenous lipid emulsion, saline, and no treatment. An increase in arterial blood pressure underlay the recovery in both lipid emulsion-treated groups. Heart rates remained depressed in all four groups throughout the observation period. Model predictions mirrored the experimental recovery, and the model that combined volume, sequestration, and inotropy predicted in vivo results most accurately.
Conclusion:
Intravenous lipid emulsion accelerates cardiovascular recovery from bupivacaine toxicity in a dose-dependent manner, which is driven by a cardiotonic response that complements the previously reported sequestration effect.
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