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Bupivacaine is a potent local anesthetic with unique characteristics from the amide group of local anesthetics. Local anesthetics are used in regional anesthesia, epidural anesthesia, spinal anesthesia, and local infiltration. Local anesthetics generally block the generation of the action potential in nerve cells by increasing the threshold for electrical excitation. This activity reviews the mechanism of action, adverse event profile, toxicity, dosing, pharmacodynamics, and monitoring of bupivacaine, pertinent for members of the interprofessional team for the treatment of patients when local anesthesia is warranted. Objectives: Outline the indications for the use of bupivacaine. Review the mechanism of action of bupivacaine. Explain the contraindications to using bupivacaine. Summarize interprofessional team strategies for improving care coordination and communication to advance pain control and improve outcomes when using bupivacaine. Access free multiple choice questions on this topic.

Most local anesthetics produce similar signs and symptoms, but the ratio of neurotoxicity to cardiotoxicity may differ, with bupivacaine being the most cardiotoxic. The incidence of toxicity is rare: 1 to 1000 to 1 to 10000. Be concerned for local anesthetic toxicity (LAST) with abnormal cardiovascular or neurological signs and symptoms. The site of administration of local anesthetic also influences the risk of toxicity. Unintended direct intravenous injection or rapid vascular uptake of the drug is the most common reason for bupivacaine toxicity, which has an upper limit of 2.5 to 3.5 mg/kg upper limit of dosing. Depending on the vascularity of the injection site and the technique, toxicity of the medication can occur if administering the upper limit of the dosing recommendations. Signs and symptoms of toxicity may occur rapidly or be delayed. Rarely, patients exhibit toxicity to bupivacaine in doses much lower than the suggested upper limits of dosing. This toxicity appears to be due to a rare condition related to l-carnitine deficiency. Patients affected may exhibit cardiac toxicity at doses as low as 1.1 mg kg of bupivacaine injected cutaneously. Case reports exist describing these cases of low dose toxicity in patients later discovered to be deficient in l-carnitine. A rat study demonstrated this model and found that the administration of supplemental l-carnitine could reverse this effect.[8] Most-to-Least Toxic Sites Intravenous>Intercostal>Caudal>Epidural>Interfascial plane blocks of the abdominal wall (TAP)> Psoas compartment blocks>Sciatic blocks>Cervical plexus block>Brachial plexus block. Pathophysiology At therapeutic levels, local anesthetics block voltage-gated Na-channels at the alpha subunit inside the channel, preventing Na+ influx, preventing depolarization, and action potential generation. They affect cardiac Na+-channels and neurons in the brain at toxic levels, blocking K+, Ca2+, and NMDA receptors. Local anesthetics also interfere with cellular processes, including oxidative phosphorylation, free fatty acid utilization, and cAMP production. Toxic levels of local anesthetics on the heart lead to conduction irregularities, impaired cardiac contractility, and the loss of vascular tone secondary to extreme vasodilation. Signs and Symptoms Neurological

At therapeutic levels, local anesthetics block voltage-gated Na-channels at the alpha subunit inside the channel, preventing Na+ influx, preventing depolarization, and action potential generation. They affect cardiac Na+-channels and neurons in the brain at toxic levels, blocking K+, Ca2+, and NMDA receptors. Local anesthetics also interfere with cellular processes, including oxidative phosphorylation, free fatty acid utilization, and cAMP production. Toxic levels of local anesthetics on the heart lead to conduction irregularities, impaired cardiac contractility, and the loss of vascular tone secondary to extreme vasodilation. Signs and Symptoms Neurological Early - perioral tingling, tinnitus, blurry vision, and tongue paresthesias, advances to CNS depression (slurred speech and drowsiness), Late -  agitation, confusion, AMS, seizures. Depressive phase - coma and respiratory depression. Cardiovascular Hypertension and tachycardia: intermediate myocardial depression and hypotension. Terminal - vasodilation, severe hypotension, dysrhythmias, conduction blocks, and asystole. Hypercarbia It lowers the seizure threshold and increases cerebral blood flow, leading to more local anesthetic into the brain. Acidosis also impairs the protein binding of local anesthetic and leads to a more free fraction in plasma, which leads to more local anesthetic delivery to the brain. Treatment

Hypertension and tachycardia: intermediate myocardial depression and hypotension. Terminal - vasodilation, severe hypotension, dysrhythmias, conduction blocks, and asystole. Hypercarbia It lowers the seizure threshold and increases cerebral blood flow, leading to more local anesthetic into the brain. Acidosis also impairs the protein binding of local anesthetic and leads to a more free fraction in plasma, which leads to more local anesthetic delivery to the brain. Treatment Treatment of bupivacaine toxicity has long been challenging due to its profound neurologic and cardiac toxicity. Previously, treatment had been supportive, with standard cardiopulmonary resuscitation, airway management, and seizure control with quick-acting GABA agonists such as midazolam. Because of the long duration of action for bupivacaine, toxicity was especially problematic. In centers where cardiopulmonary bypass was readily available, it was used to support the toxic patient until the drug was adequately metabolized and cleared, which may take hours. In the early 2000s, landmark research by Guy Weinberg revealed that lipid emulsion, such as the type that serves as the carrier for total parenteral nutrition formulations, was effective in rescuing laboratory animals from bupivacaine toxicity. The profound results in animals (mice and dogs) led to several case reports where lipid emulsion was used as a last resort in human patients with profound cardiovascular collapse following nerve blocks with long-acting local anesthetics such as bupivacaine and ropivacaine.  Over the following 15 years, the treatment with lipid emulsion became widely accepted as effective and was adopted by the American Society of Regional Anesthesia as the standard for treating local anesthetic systemic toxicity (LAST) and has been adopted into their treatment algorithm. Once only used as a last resort treatment, it is now widely used as a first-line treatment for these patients. Facilities that administer local anesthetics should have lipid emulsions readily available for emergencies. Interestingly, high dose epinephrine has shown associations with decreased effectiveness of lipid emulsion in the treatment of LAST. This evidence further emphasizes the importance of early treatment with lipid emulsion when LAST is suspected. Detailed treatment algorithms are available through the American Society of Regional Anesthesia's website.[9] The current dosing recommendations for lipid emulsion 20% are as follows:

Treatment of bupivacaine toxicity has long been challenging due to its profound neurologic and cardiac toxicity. Previously, treatment had been supportive, with standard cardiopulmonary resuscitation, airway management, and seizure control with quick-acting GABA agonists such as midazolam. Because of the long duration of action for bupivacaine, toxicity was especially problematic. In centers where cardiopulmonary bypass was readily available, it was used to support the toxic patient until the drug was adequately metabolized and cleared, which may take hours. In the early 2000s, landmark research by Guy Weinberg revealed that lipid emulsion, such as the type that serves as the carrier for total parenteral nutrition formulations, was effective in rescuing laboratory animals from bupivacaine toxicity. The profound results in animals (mice and dogs) led to several case reports where lipid emulsion was used as a last resort in human patients with profound cardiovascular collapse following nerve blocks with long-acting local anesthetics such as bupivacaine and ropivacaine.  Over the following 15 years, the treatment with lipid emulsion became widely accepted as effective and was adopted by the American Society of Regional Anesthesia as the standard for treating local anesthetic systemic toxicity (LAST) and has been adopted into their treatment algorithm. Once only used as a last resort treatment, it is now widely used as a first-line treatment for these patients. Facilities that administer local anesthetics should have lipid emulsions readily available for emergencies. Interestingly, high dose epinephrine has shown associations with decreased effectiveness of lipid emulsion in the treatment of LAST. This evidence further emphasizes the importance of early treatment with lipid emulsion when LAST is suspected. Detailed treatment algorithms are available through the American Society of Regional Anesthesia's website.[9] The current dosing recommendations for lipid emulsion 20% are as follows: For a patient greater than 70 kg, bolus 100 mL of lipid emulsion 20% rapidly over 2 to 3 minutes and then infuse 200 to 250 mL over the next 15 to 20 minutes. Redosing may be necessary up to a maximum dose of 12 mL/kg.

Treatment of bupivacaine toxicity has long been challenging due to its profound neurologic and cardiac toxicity. Previously, treatment had been supportive, with standard cardiopulmonary resuscitation, airway management, and seizure control with quick-acting GABA agonists such as midazolam. Because of the long duration of action for bupivacaine, toxicity was especially problematic. In centers where cardiopulmonary bypass was readily available, it was used to support the toxic patient until the drug was adequately metabolized and cleared, which may take hours. In the early 2000s, landmark research by Guy Weinberg revealed that lipid emulsion, such as the type that serves as the carrier for total parenteral nutrition formulations, was effective in rescuing laboratory animals from bupivacaine toxicity. The profound results in animals (mice and dogs) led to several case reports where lipid emulsion was used as a last resort in human patients with profound cardiovascular collapse following nerve blocks with long-acting local anesthetics such as bupivacaine and ropivacaine.  Over the following 15 years, the treatment with lipid emulsion became widely accepted as effective and was adopted by the American Society of Regional Anesthesia as the standard for treating local anesthetic systemic toxicity (LAST) and has been adopted into their treatment algorithm. Once only used as a last resort treatment, it is now widely used as a first-line treatment for these patients. Facilities that administer local anesthetics should have lipid emulsions readily available for emergencies. Interestingly, high dose epinephrine has shown associations with decreased effectiveness of lipid emulsion in the treatment of LAST. This evidence further emphasizes the importance of early treatment with lipid emulsion when LAST is suspected. Detailed treatment algorithms are available through the American Society of Regional Anesthesia's website.[9] The current dosing recommendations for lipid emulsion 20% are as follows: For a patient greater than 70 kg, bolus 100 mL of lipid emulsion 20% rapidly over 2 to 3 minutes and then infuse 200 to 250 mL over the next 15 to 20 minutes. Redosing may be necessary up to a maximum dose of 12 mL/kg. For a patient of less than 70 kg, bolus 1.5 mL/kg lipid emulsion 20% rapidly over 2 to 3 minutes, followed by an infusion of 0.25 mL/kg/min for ideal body weight to an upper limit of 12 mL/kg.

For a patient greater than 70 kg, bolus 100 mL of lipid emulsion 20% rapidly over 2 to 3 minutes and then infuse 200 to 250 mL over the next 15 to 20 minutes. Redosing may be necessary up to a maximum dose of 12 mL/kg. For a patient of less than 70 kg, bolus 1.5 mL/kg lipid emulsion 20% rapidly over 2 to 3 minutes, followed by an infusion of 0.25 mL/kg/min for ideal body weight to an upper limit of 12 mL/kg. A cardiopulmonary bypass should also still be considered early in case other treatments are ineffective.

Bupivacaine is administered to patients by many healthcare professionals, including the surgeon, anesthesiologist, pain specialist, emergency department physician, and nurse practitioner. However, all interprofessional healthcare team members involved in administering and dispensing the drug must know its potential side effects and toxicity. Resuscitative equipment must be in the room at the time of the injection, and surgical nurses must be familiar with the proper use of this equipment in an emergency. The most common reason for a complication is an injection of the drug into the artery or vein, which can result in adverse cardiac and CNS effects.[10][11] Pharmacists can be involved in preparing the agents and verifying proper dosing and administration, working with the anesthesiologist or nurse anesthetist. They can also assist in cases of toxicity with the needed drugs to address toxic states. Bupivacaine use requires an interprofessional team approach, including physicians, specialists, specialty-trained nurses, and pharmacists, all collaborating across disciplines to achieve optimal patient results. [Level 5]