(582dz) Positive Inotropy – a Likely Mechanism for Lipid Reversal of Local Anesthetic Toxicity

In small animal experiments and a growing number of clinical cases, lipid therapy – the intravenous infusion of an oil-in-water emulsion – has been observed to rapidly reverse the cardiotoxic effects of lipophilic drugs. Patients experiencing otherwise fatal poisonings have recovered a spontaneous cardiac function in as little as 60 seconds following prolonged cardiac arrest.  The mechanism by which toxicity reversal by lipid infusion occurs is poorly understood.  The variety of toxins and doses to which patients are exposed (as well as the obvious ethical impossibility of inducing cardiac failure) limits the opportunity to conduct clinical trials for lipid resuscitation. In vitro observations support the often-cited lipid sink theory of therapeutic action – oil droplets are thought sequester lipophilic molecules from the aqueous blood plasma.  However, competing theories exist.  In small animal experiments, IV lipid has been observed to act as a positive inotrope – directly improving cardiac function.  It is proposed that this effect may be primarily responsible for the dramatic recoveries observed in lipid reversal of anesthetic-induced cardiotoxicity. In an effort to quantitatively probe the merits of lipid sequestering vs. inotropy as a dominating mechanism of resuscitation, a physiologically based pharmacokinetic-pharmacodynamic  model (PBPK-PD) has been developed.

The PBPK-PD model was developed in-house.  For both the human model and rat model, the simulation represents both bupivacaine and lipid pharmacokinetics and accounts for plasma binding of bupivacaine by 2 classes of plasma proteins, red blood cells, and plasma lipid.  In all cases, bupivacaine binding is modeled as concentration-dependent and saturable. The pharmacodynamic model of cardiac function allows for the negative chronotropic effect of bupivacaine, the positive inotropic effect of lipid, and the flow promoting influence of IV fluid infusion.  Observables include heart rate, mean arterial pressure, and cardiac output.  The pharmacokinetic model includes no fitting parameters.  The PD model includes a negative feedback control loop whose parameters are estimated from in vivo small animal data.  The rat PBPK-PD model was used to simulate a low-dose scheme known to cause toxicity that resolves without CPR intervention. Lipid therapy was simulated as operating via (i) a sequestering mechanism, (ii) a positive inotropic mechanism, and (iii) a combination of the two.

The human bupivacaine PK model yielded quantitative agreement with available pharmacokinetic data. The lipid sink mechanism was predicted to yield (1) an increase in total plasma concentration, (2) a decrease in unbound concentration, and (3) a decrease in tissue content of bupivacaine.  Bupivacaine concentration falls rapidly in the heart, but by less than 15%.  In the rat model, the inotropic effect resulted in a decrease in tissue concentration, but yielded a more rapid recovery of cardiac function. The combined effect of the sink and inotropic mechanisms was similar to that of the inotropic mechanism alone.  This study suggests that, in isolation, the lipid sink effect may not be sufficient to guarantee a reversal of local anesthetic systemic toxicity.  The positive inotropic effect of lipid is, however, predicted to promote rapid recovery of cardiac function.