Resuscitation with lipid emulsion: dose-dependent recovery from cardiac pharmacotoxicity requires a cardiotonic effect

Abstract

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.

Conflict of interest statement

Conflicts of Interest: Guy Weinberg holds a US Patent related to lipid resuscitation. Guy Weinberg & Israel Rubinstein are co-founders of ResQ Pharma, LLC, Northbrook, Illinois.

Figures

Figure 1

Baseline and 10-min lactate levels for the combined treatment conditions (ILE = combined 30% intravenous lipid emulsion & 20% intravenous lipid emulsion). At 10 min, Saline\Null was elevated relative to baseline (p < 0.01) and relative to the 10-min lactate levels in the combined ILE group (** p < 0.01). Ten-minute ILE levels were no different from baseline levels.

Figure 2

Graphic representation of time to 50% recovery for rate-pressure-product (RPP), mean arterial pressure (MAP), carotid flow (Flow) and heart rate (HR) in response to treatment with 30% intravenous lipid emulsion (ILE30), 20% intravenous lipid emulsion (ILE20), Saline and nothing (Null). Accompanying recovery data are depicted in table 1.(*** p < 0.001)

Figure 3

(A) Median plot of mean arterial pressure normalized to baseline (average over 20-s prior to bupivacaine infusion; 10 mg/kg bupivacaine infusion at t = 0). Response to four different intravenous infusions starting at t = 30 s: 4mL/kg 30% intravenous lipid emulsion (ILE30), 4mL/kg 20% intravenous lipid emulsion (ILE20), 4mL/kg 0.9% saline (Saline), and no treatment (Null). (B) Plot of time points when rate-pressure-product is different from baseline (p < 0.05) based on paired Mann-Whitney U-test with 1-s time-scale for 30% intravenous lipid emulsion, 20% intravenous lipid emulsion, saline, and null. (C,D) Same as A & B, but for median heart rate. (E,F) Same as A & B but for median rate-pressure-product (G,H) Same as A & B, but for carotid blood flow.

Figure 4

(A) Plot of both median rate-pressure-product (RPP) and median carotid flow (Flow) for 30% intravenous lipid emulsion (ILE30) and saline treatments. (B) Plot of median carotid resistance relative to prebupivacaine baseline with accompanying 90% confidence intervals (90%CI) aligned to the recovery of 50% flow (0.5× flow); alignment was conducted on individual animals and aggregated post-alignment. (C) Plot of median carotid flow (Relative Flow) relative to prebupivacaine baseline with accompanying 90% confidence intervals (90%CI) aligned to the recovery of 50% flow (0.5×). (D) Plot of median mean-arterial-pressure relative to prebupivacaine baseline with accompanying 90% confidence intervals (90%CI) aligned to the recovery of 50% mean arterial pressure (0.5× MAP).

Figure 5

Pharmacokinetic-pharmacodynamic model of cardiac output relative to baseline (1.0) following bupivacaine-induced cardiac depression and subsequent recovery with different treatments. (A) Treatment-specific curves matched to experimental conditions for 30% intravenous lipid emulsion (ILE30), 20% intravenous lipid emulsion (ILE20), 0.9% Saline (Saline) and no treatment (Null). For ILE30 and ILE20, the modeled response includes mathematical contributions from a volume effect, a sink effect and an inotropic effect. (B) Mechanism-specific contributions to recovery from bupivacaine cardiac depression following an infusion of 30% intravenous lipid emulsion; mechanisms represented are no effect (Null), volume effect only (Volume; equivalent to 0.9% Saline model), sink & volume, inotropy & volume, and a combination of sink, inotropy & volume. Specific mechanisms and combinations were probed by turning on and off individual mathematical components as described in the Computational Modeling section of the methods.

Figure 6

(A) 95% confidence-interval (95%CI) and 68% confidence interval (68%CI) generated with experimental rate-pressure-product data for 30% intravenous lipid emulsion (ILE30) experimental treatment overlaid with pharmacokinetic-pharmacodynamic model predictions. (B) Continuous plot of time when the pharmacokinetic-pharmacodynamic curves for volume & sequestration (sink + vol), volume & inotropy (inotropy + vol), and volume/inotropy/sequestration (ino + sink + vol) remain within the experimental confidence interval. (C) 95% confidence-interval and 68% confidence interval (68%CI) generated with experimental rate-pressure-product data for saline treatment overlaid with pharmacokinetic-pharmacodynamic prediction for the volume resuscitation mechanism. (D) Continuous plot of time when volume curve remains within the experimental confidence interval.