Potential Side Effect of Inadvertent Intravascular Administration of Liposomal Bupivacaine
Abstract
The proposed project will examine 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. EXPAREL has recently gained Food and Drug Administration approval exclusively for wound infiltration; however, if it proves to be safe and effective, it might become a valuable option for single injection, extended duration peripheral nerve blocks. The unique benefit of the liposomal EXPAREL is that it enables slower, gradual release of the active ingredient, allowing a longer duration of action after a single administration compared to the conventional bupivacaine. If proven to be safe and effective, it could be a viable alternative to continuous infusion of local anesthetics via catheters that can be difficult to place, require expensive pumps and close monitoring, and may be a site for infection. However, potential adverse events might arise during these procedures if the drug is accidentally injected into the vasculature. The bupivacaine component of EXPAREL can provoke local anesthetic systemic toxicity (LAST), which in severe cases might cause convulsions and even heart failure. Although the frequency of such toxic events is less than 0.2%, they are difficult to treat and are potentially fatal. For this reason, it is important to determine the tolerable and toxic doses of EXPAREL in animal studies before human clinical trials can be started. It is also necessary to study the effectiveness of currently recommended rescue protocols for accidental intravascular injection of local anesthetics, because certain properties of EXPAREL differ from the conventional solution of bupivacaine. Intravenous lipid emulsion (ILE) has been shown to be effective in bupivacaine toxicity, and the American Heart Association has recommended its use in the Advanced Cardiac Life Support (ACLS) guidelines. However, in EXPAREL the bupivacaine is encapsulated in liposomes, which might decrease the ability of the intravenously administered lipid emulsion to neutralize the systemic toxic effects. Therefore, we propose to conduct experiments to compare the effectiveness of various resuscitative measures using chest compressions alone, supplemented with lipid emulsion, epinephrine, vasopressin, and their combinations in rats to find the optimal treatment for EXPAREL overdose. The liposomal component of EXPAREL might also have a potential side effect: complement activation related pseudo-anaphylaxis (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 intend to analyze the cardiovascular and immunological reactions following intravenous administration of liposomal bupivacaine in swine, the most sensitive model currently available. Based on the outlined series of experiments, we will be able to evaluate the safety profile of liposomal bupivacaine for peripheral nerve blocks in terms of accidental intravascular administration. If EXPAREL proves to be safe and effective as a long-acting, single-injection local anesthetic for peripheral nerve blocks, it would provide a valuable alternative to current opioid analgesics for severe pain management by the medic/corpsman on the battlefield and remote locations as well as for management of acute pain under the care of a clinician in non-deployed settings.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510130
Entities
People
- Chester Buckenmaier Iii
Organizations
- Uniformed Services University of the Health Sciences
- United States Army