Potential Side Effect of Inadvertent Intravascular Administration of Liposomal Bupivacaine

The project examines the safety aspects of the use of EXPAREL for peripheral nerve blocks. EXPAREL is a novel form of the commonly used bupivacaine, which if injected into the close proximity of nerves, can block the conduction of pain signals, thereby acting as a local anesthetic. Potential adverse events might arise during these procedures if the drug is accidentally injected into the vasculature. These adverse events may arise for at least two distinct reasons 1. The bupivacaine component of EXPAREL can provoke local anesthetic systemic toxicity LAST, which in severe cases might cause convulsions and even heart failure. For this reason, it is important to determine the tolerable and toxic doses of EXPAREL, and to study the effectiveness of currently recommended rescue protocols for accidental intravascular injection of local anesthetics in animal studies before human clinical trials can be started. 2. The liposomal component of EXPAREL might also have a potential side effect complement activation related pseudoanaphylaxis CARPA, a hypersensitivity reaction that is triggered by some liposomal drugs, and can occur at the first administration, without prior sensitization, and can have a severe outcome. To study the possibility of these reactions we analyze the cardiovascular and immunological reactions following intravenous administration of liposomal bupivacaine in swine, the most sensitive model currently available. During the first year of the study we administered Exparel and bupivacaine to rats intravenously as a continuous infusion. Asystole was observed at a dose of 43 mgkg with Exparel and at a dose of 13.5 mgkg with bupivacaine. During the period covered by this report we used an up-down method to identify the minimum lethal bolus dose to induce asystole, which was 40 mgkg for Exparel and 20 mgkg for bupivacaine. During the first year of the project we identified that intravenously administered Exparel in swine caused severe hemodynamic alteration