The lipophilicity of local anesthetics (LAs) determines the drug-specific analgesic potency and accounts for decreased metabolism. In addition, lipid solubility has a strong impact on their specific (cardio-) toxicity.1,2 Results from different studies suggest a close correlation between lipid solubility, analgesic potency, and specific systemic toxicity of LAs (e.g., bupivacaine > ropivacaine > mepivacaine).2–4
The therapy for LA-induced cardiac arrest is still a challenging clinical problem. Next to providing advanced life support according to current guidelines, the infusion of insulin and glucose (with or without the addition of potassium) or lidocaine, respectively, have been proposed, but clinical efficacy has never been proven.5,6 Recently, the infusion of lipid emulsions has been introduced into clinical practice to treat cardiac arrest, especially after bupivacaine-induced cardiac toxicity. According to Weinberg et al.,7,8 the so-called “lipid sink” effect is suggested to be the basic mechanism of this therapeutic approach. They hypothesized that fat droplets form a lipid compartment, separate from the plasma aqueous phase, into which a lipophilic substance such as bupivacaine might dissolve. Thus, bupivacaine might be drawn into this lipid sink, reducing the aqueous plasma concentration.
As this mechanism is suggested to depend on the lipid solubility of LAs, it can be assumed that its extent varies depending on the physico-chemical properties of the administered drugs. Therefore, it was the aim of this study to assess the impact of lipid infusion on cardiac recovery after bupivacaine-, ropivacaine-, and mepivacaine-induced cardiac arrest.
Preparation and Measurements
Approval from the Institutional Animal Care Committee of the University of Goettingen was obtained before initiation of this study. Fifteen male Wistar rats (234 ± 7 g) were injected intraperitoneally with 100 mg/kg ketamine, 2.5–5 mg/kg xylazine hydrochloride, and 1000 U heparin and were decapitated when unresponsive to noxious stimulation. After sternotomy, the heart was rapidly excised during continuous retrograde aortic perfusion with a cold, oxygenated, and modified Krebs-Ringer solution (KRS), saturated with 95% O2 and 5% CO2, and transferred to a Langendorff apparatus (Hugo Sachs Electronic KG, March-Hugstetten, Germany). A description for this model and the surgical procedures has been reported in detail.9 The KRS was filtered (5-μm pore-size filter disk, Sigma-Aldrich®, Munich, Germany) in-line and had the following control composition: Na+ 140 mM; K+ 4.5 mM; Mg2+ 1.2 mM; Ca2+ 2.5 mM; Cl− 134 mM; HCO3− 15.5 mM; H2PO4− 1.2; EDTA 0.05 mM; glucose 11.5 mM; pyruvate 2 mM; mannitol 10 mM; and insulin 5 U/L. Perfusion was maintained at a constant flow of 12 mL/min by a roller pump (Ismattec®, Glattbrugg, Switzerland). Perfusate and heart temperatures were maintained at 37.0°C ± 0.2°C throughout the experiment. Oxygen tension and electrolytes in the coronary inflow and outflow were measured using a self-calibrating gas analyzer (AVL OMNI 9®, Roche Diagnostic, Mannheim, Germany). Mean aortic inflow pH, CO2 tension (Pco2), and O2 tension (Po2) were 7.4 ± 0.02, 34 ± 1 mm Hg, and 602 ± 13 mm Hg, respectively.
A thin, saline-filled latex balloon (Hugo Sachs Electronic KG) was inserted into the left ventricle and was attached to a metal cannula. The connection of this cannula to a pressure transducer (Isotec®, Hugo Sachs Electronic KG) provided measurement of isovolumetric systolic left ventricular pressure (LVP) development. Balloon volume was adjusted to maintain an initial diastolic LVP of 0 mm Hg during the control period so that any increase in diastolic LVP reflected an increase in left ventricular wall stiffness or diastolic contracture. Once the balloon volume was set, it remained constant throughout the experiment. Two pairs of bipolar silver electrodes (Teflon-coated silver, diameter 125 μm, Cooner Wire, Chatsworth, CA) were attached to the right atrium and the pulmonary conus to monitor intracardiac electrograms from which spontaneous sinoatrial and ventricular rates were measured as noted previously.9 Heart rate, LVP, coronary inflow, and pressure were continuously measured, displayed on a screen, and recorded digitally on a hard drive for 10 s. The rate-pressure product (RPP = [left ventricular systolic pressure − left ventricular diastolic pressure] × heart rate) was calculated.
After stabilization for 20 min, the hearts were randomly assigned to three groups (five hearts each). Subsequently, they were perfused with a KRS containing, in relation to their cardiac toxicity, “equipotent” doses of bupivacaine (250 μM; AstraZeneca®, Södertälje, Sweden), ropivacaine (500 μM; AstraZeneca), and mepivacaine (1000 μM; AstraZeneca), respectively, until a 2-min period of asystole was obtained.2,3 Thereafter, the perfusion solution was changed to KRS alone (control groups: Bupi, Ropi, and Mepi) or KRS with the addition of lipids (treatment groups: Bupi + Lipo, Ropi + Lipo, and Mepi + Lipo) at a dose of 0.25 mL · kg−1 · min−1 (Lipofundin® MCT 20%, B. Braun, Melsungen, Germany) for 60 min.10–12 Lipid emulsion was added by a perfusion pump (Braun® perfusor compact, Melsungen, Germany) positioned directly above the heart. Each heart was perfused twice by one local anesthetic randomly followed by control or treatment perfusion (Fig. 1).
The selected end points were the recovery times from cardiac arrest (zero time) to (i) first spontaneous heart beat (supraventricular or ventricular), (ii) the start of ventricular, supraventricular, or sinus rhythm, and recovery of (iii) heart rate and (IV) RPP to 90% of baseline values.12
For statistical analysis, we applied the Kolmogorov-Smirnov test to confirm normal distribution for each group. Raw data from each selected end point were compared by unpaired Student’s t-test or by Wilcoxon-Mann-Whitney test, respectively. P < 0.05 was considered to be statistically significant. All data in the text, tables, and figures are displayed as mean ± sem.
Control values for bupivacaine, ropivacaine, and mepivacaine showed no statistical differences for heart rate (control groups: Bupi: 273 ± 6, Ropi: 277 ± 7, and Mepi: 271 ± 10 bpm and treatment groups: Bupi + Lipo: 263 ± 5, Ropi + Lipo: 274 ± 8, and Mepi + Lipo: 273 ± 11 bpm, respectively) and RPP (control groups: Bupi: 27964 ± 1209, Ropi: 28983 ± 1010, and Mepi: 29162 ± 1274 mm Hg · bpm and treatment groups: Bupi + Lipo: 26483 ± 1002, Ropi + Lipo: 28809 ± 1150, and Mepi + Lipo: 28254 ± 1506 mm Hg · bpm, respectively) after stabilization.
Starting the KRS perfusion containing bupivacaine, ropivacaine, or mepivacaine, cardiac arrest occurred after 247 ± 9 s, 224 ± 8 s, and 262 ± 10 s, respectively, in the control groups, and after 253 ± 9 s, 226 ± 9 s, 264 ± 11 s in the treatment groups, respectively. There were no statistically significant differences among the groups.
The times from the start of reperfusion to the first cardiac action, the start of ventricular, supraventricular, or sinus rhythm are shown in Figure 2 for both groups. Lipid infusions did not decrease recovery time in bupivacaine, ropivacaine, or mepivacaine-treated hearts with regard to the first heart beat or rhythm. In contrast, however, lipid infusions significantly improved recovery times to supraventricular and sinus rhythm, respectively, in the bupivacaine group. These effects were not seen in the ropivacaine or mepivacaine groups (Fig. 2).
Heart rate and RPP recovered significantly faster in bupivacaine-treated hearts (when compared with the control group at 90% of baseline values). However, these effects were not seen after ropivacaine- or mepivacaine-induced cardiac arrest (Fig. 3).
In this study, we compared the effects of lipid infusion on cardiac recovery after mepivacaine-, ropivacaine-, and bupivacaine-induced cardiac arrest. We found that lipid emulsion had no influence on the recovery time from LA-induced cardiac arrest to the return of first signs of cardiac activity. But, after the return of heart rhythm, lipid emulsions significantly decreased the recovery time for heart rate and RPP in bupivacaine-induced cardiac toxicity, but not in mepivacaine- or ropivacaine-induced cardiac toxicity.
Mepivacaine, ropivacaine, and bupivacaine chemically belong to the group of pipecoloxylidides and have different lipophilic properties which closely correlate with their different anesthetic potency and their specific cardiac toxicity. Structurally, these differences are the result of different alkylic side chains on the piperidine ring (butylic [–C4H9] for bupivacaine, propylic [–C3H7] for ropivacaine, and methylic [–CH3] for mepivacaine).13 Consequently, a rank order of lipid solubility, analgesic potency, and toxicity of bupivacaine > ropivacaine > mepivacaine is suggested.3,4,14
The mechanism of the postulated lipid sink effect is still unclear. One theory is that the lipid infusion creates a lipid plasma phase that essentially “extracts” the lipid soluble bupivacaine molecules from the aqueous plasma phase, making them unavailable to the tissue.15 Consequently, the reduced “free” bupivacaine concentration in the plasma aqueous phase increases the diffusion gradient between “intoxicated” tissue and blood, thereby facilitating faster return of spontaneous heart rhythm. Therefore, we hypothesized that if the lipid sink effect is dependent on the lipophilicity of LAs, it may be less pronounced for less lipophilic LAs.
In this study, the effects of lipid infusion on recovery from cardiac arrest after infusion of the highly lipophilic bupivacaine and the less lipophilic drugs ropivacaine and mepivacaine at equipotent doses, respectively, were assessed. Pipecoloxylidides are optimal for systematically studying lipophilic effects, because their chemical structure only differs in the length of an alkylic side chain. This fact, however, can explain marked differences in lipophilic properties and, consequently, analgesic potency and specific systemic toxicity among these drugs (bupivacaine > ropivacaine > mepivacaine).2–4
One of the selected end points was the recovery time from the start of reperfusion to first sign of cardiac activity (Fig. 2). Lipid infusion did not cause an accelerated return of a spontaneous rhythm of the heart for mepivacaine, ropivacaine, or bupivacaine. These results are in contrast to data from Weinberg et al.,12 because they showed that lipid-treated isolated hearts showed a faster return of a “first beat” after cardiac arrest induced by a bolus of bupivacaine. However, mepivacaine and ropivacaine were not tested. One reason for this obvious discrepancy may be different study protocols, e.g., with regard to the length of time of the local anesthetic infusions, bupivacaine concentration, and duration of cardiac arrest.
After the return of heart rhythm, however, our study showed an accelerated time of recovery of heart rate and RPP in the bupivacaine-treated group, but not in the ropivacaine- or the mepivacaine-treated group (compared with control group at 90% of baseline values). These data go along with other isolated heart studies evaluating bupivacaine cardiac toxicity.12 Consequently, with regard to our hypothesis, the lipophilicity-dependent lipid sink effect was not detected in the less lipophilic mepivacaine- and ropivacaine-induced cardiac toxicity.
Our results demonstrate no beneficial effect of lipid infusion on mepivacaine- or ropivacaine-induced cardiac arrest in the isolated heart, which is in contrast to clinical observations.16,17 These case reports assume a strong correlation between cardiac arrest and local anesthetic drug, and furthermore between lipid infusion and return of spontaneous circulation, although other reasons for cardiac arrest and return of spontaneous circulation cannot be methodically excluded.
The isolated heart model offers the advantage to focus on direct cardiotoxic effects of LAs. But, of course, reactions from the central nervous system exerting indirect toxic effects on the heart (e.g., bradycardia, hypotension) might be underestimated, and interactions with lipid treatment are undetectable in the isolated heart.2 Additionally, because, in this study, hearts were perfused with KRS with a balanced pH and adequate oxygen supply, the present results might differ in a model with a shift of pH because of a metabolic and respiratory acidosis and a reduced oxygen supply because of cardiac arrest.8 This is especially important with regard to the different pKa values of LA influencing their penetration modalities.
In conclusion, these data show that effects of lipid infusion on LA-induced cardiac arrest are not uniform and depend on the physico-chemical properties of the administered LAs. In our model, lipid infusion did not accelerate the return of any heart rhythm in any LA-induced cardiac toxicity. The crucial lipid sink effect only seems to be relevant in bupivacaine-induced cardiac toxicity, but not in mepivacaine- or ropivacaine-induced cardiac toxicity. Therefore, we conclude that lipophilicity of LAs has a marked impact on the efficacy of lipid infusions to treat cardiac arrest induced by these drugs. Further studies are needed to define the molecular effect of lipid infusion in local anesthetic-induced cardiac toxicity.
The authors thank AstraZeneca®, Södertälje, Sweden, for providing dry matter of ropivacaine, bupivacaine, and mepivacaine.
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