PHARMACOLOGY FACTS
Local Anesthetics Julie Golembiewski, PharmD EFFECTIVE PERIOPERATIVE PAIN MANAGEMENT is important for patient comfort and satisfaction and contributes to improved healing, faster patient mobilization, shorter hospital stays, and lower health care costs.1 Systemic opioids are a mainstay of perioperative pain management, but their use is often associated with adverse effects such as nausea, vomiting, constipation, and pruritus. Whenever possible, a multimodal approach (administration of two or more drugs that act via different mechanisms to provide analgesia) to perioperative pain management should be used to optimize analgesia and minimize opioid adverse events.1,2 For surgical patients, local anesthetics are a key component of a multimodal analgesic regimen. Local anesthetics act by diffusing through the cell membranes and binding to sodium channels to block electrical impulses (action potentials) necessary for nerve conduction. Local anesthetics can be administered by infiltration around the surgical incision site, injected around a peripheral nerve, injected into the epidural space, or injected into the subarachnoid space. Although local anesthetics can be administered topically, this route of administration is generally not used for postoperative pain management.
plasma esterases to their primary metabolite, para-aminobenzoic acid. The amide-type local anesthetics, on the other hand, undergo metabolism in the liver. Local anesthetics vary in their lipid solubility, degree of protein binding, and dissociation constant (pKa). Ropivacaine has greater lipid solubility than lidocaine, allowing a lower milligram dose to achieve a comparable effect (eg, ropivacaine is prepared as a 0.2% or 0.5% solution, whereas lidocaine is prepared as a 1% or 2% solution). Ropivacaine has a high affinity for plasma proteins (94% bound to plasma proteins), prolonging its duration of action compared with lidocaine (55% bound to plasma proteins). The agents with a lower pKa, such as lidocaine and mepivacaine, have a greater portion of molecules in the uncharged (active) form, resulting in a more rapid onset of action than an agent with a higher pKa (eg, ropivacaine).3-5
Novel Formulation of Bupivacaine
Local anesthetics have a lipophilic region and a hydrophilic region linked by either an ester (-CO-) or an amide (-NHC-) bond. The ester-type local anesthetics are quickly hydrolyzed by
Bupivacaine liposome injectable suspension (Exparel; Pacira Pharmaceuticals Inc., San Diego, CA) uses the DepoFoam delivery technology. The liposomes consist of an aqueous bupivacainecontaining core encapsulated by a phospholipid bilayer. The liposomes are nonconcentric, allowing progressive breakdown and reorganization of the lipid bilayer.6,7 This DepoFoam technology extends the delivery of bupivacaine to the site giving the Exparel product a duration of action of 72 hours compared with a duration of action of 2-12 hours for bupivacaine HCl depending on the route of administration.8
Julie Golembiewski, PharmD, is a clinical associate professor, University of Illinois Hospital & Health Sciences, Chicago, IL. Conflict of interest: Julie Golembiewski is a member of a pharmacist advisory board for Pacira Pharmaceuticals, Inc. Address correspondence to Julie Golembiewski, University of Illinois Hospital & Health Sciences System, 1740 West Taylor Street, Suite 3200 (MC 515), Chicago, IL 60612-7239; e-mail address: [email protected]. Ó 2013 by American Society of PeriAnesthesia Nurses 1089-9472/$36.00 http://dx.doi.org/10.1016/j.jopan.2013.09.001
Bupivacaine liposome injectable suspension (Exparel) is infiltrated slowly into the soft tissue layers surrounding the surgical site before closure. The volume (may be diluted with up to 280 mL of saline) varies based on the size of the surgical site, but the maximum dose should not exceed 266 mg (one 20 mL vial of undiluted drug). All the tissue layers (upper portion of subcutaneous tissue, just below the fascia, and just above the fascia) should be slowly injected using a moving needle technique. If aspiration draws blood,
Classification and Pharmacokinetics
Journal of PeriAnesthesia Nursing, Vol 28, No 6 (December), 2013: pp 409-412
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JULIE GOLEMBIEWSKI
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the needle is moved to a different location until aspiration is negative. Injecting bupivacaine HCl immediately before Exparel can impact the pharmacokinetic and/or physicochemical properties of Exparel. Injecting lidocaine 20 minutes or less before Exparel or mixing lidocaine with Exparel can cause an immediate release of bupivacaine from Exparel. Other forms of bupivacaine (bupivacaine HCl) should not be administered for 96 hours after the administration of Exparel.8
Local Anesthetic Systemic Toxicity Although serious adverse effects from local anesthetics are rare, central nervous system (CNS) and/or cardiac toxicity from systemic absorption or inadvertent intravascular injection of a local anesthetic can result in disability or death. The likelihood and severity of local anesthetic systemic toxicity (LAST) is affected by the location and type of nerve block, the total dose, patient risk factors, concurrent medications, and timeliness of detection and adequacy of treatment. The classic description of LAST is a progression of symptoms beginning with CNS excitement (eg, auditory changes, metallic taste in the mouth, agitation), followed by seizures, CNS depression (eg, drowsiness, coma), cardiac toxicity (eg, hypertension, tachycardia, arrhythmia) and, ultimately, cardiac depression (eg, bradycardia, asystole, conduction blocks). Case reports, however, describe significant variation to this classic description with many patients experiencing CNS and cardiac toxicity simultaneously or experiencing cardiac toxicity without the initial signs and symptoms of CNS toxicity. The onset of LAST signs and symptoms can be fast (, 5 minutes) if there is inadvertent intravascular injection or slow (.15 minutes) if there is delayed tissue absorption of the local anesthetic.9 The clearance of commonly used local anesthetics (lidocaine, ropivacaine, and bupivacaine) is reduced by extremities of age, renal dysfunction, hepatic dysfunction, and cardiac dysfunction.9,10 Nearly half of the reports of LAST are in patients younger than 16 years of age (16%) or older than 60 years of age (30%). More than one-third of reports of toxicity involved patients with underlying cardiac, neurologic, renal, hepatic, pulmonary, or metabolic disease.9 Dose reduction and heightened vigilance may be warranted in
these patients particularly if they are at the extremes of age.9,10 The maximum recommended dose is intended to prevent an excessive amount of local anesthetic (that could result in toxicity) from being administered. The maximum recommended dose is extrapolated from animal experiments, clinical experiences, measurement of blood concentrations, case reports of toxicity, and pharmacokinetic data.10 Although not perfect, the maximum doses found in textbooks and product information are important guidelines for local anesthetics administered in the perioperative setting. An excessive amount of a local anesthetic can produce toxicity and death even when it is administered subcutaneously or topically. Administration of several liters of very dilute lidocaine with epinephrine during tumescent liposuction has resulted in deaths from lidocaine toxicity or a drug interaction with lidocaine.11 Authors of one study recommend close monitoring of patients for 24 hours after surgery because plasma concentrations of lidocaine continue to rise for 6-12 or more hours after administration.12 High concentrations of lidocaine applied topically to mucous membranes (tracheobronchial tree) or over a large area of skin (especially when an occlusive dressing is used) can also result in lidocaine toxicity (seizure, cardiac arrest, and death).13,14 Treatment of LAST includes prompt and effective airway management, benzodiazepines to suppress seizures, and if cardiac arrest occurs, Advanced Cardiac Life Support with some modifications (10-100 mcg initial epinephrine boluses; avoidance of vasopressin, calcium channel blockers, and beta blockers; and use of amiodarone for ventricular arrhythmias). After airway management, administering 20% lipid emulsion at the first signs of LAST should also be considered.9 Lipid emulsion appears to act as a ‘‘lipid sink’’ to draw the lipidsoluble local anesthetic out from within cardiac tissue, thereby improving cardiac conduction, contractility, and coronary perfusion.15
Methemoglobinemia Local anesthetics are indirect oxidizers of the iron moiety within the hemoglobin molecule, forming methemoglobin that cannot transport oxygen.
PHARMACOLOGY FACTS
411
When methemoglobin concentrations exceed 15% of the circulating hemoglobin, there is less functional hemoglobin to transport oxygen to tissues, and the patient begins to experience symptoms. As the methemoglobin level rises, cyanosis, altered mental status, tachypnea, tachycardia, respiratory compromise (requiring tracheal intubation or tracheotomy), seizures, and coma may occur. The patient’s skin and mucous membranes appear bluish, gray, or pale; chocolate-colored blood suggests methemoglobinemia, although other colors may be found.16 Because the pulse oximeter cannot detect more than two wavelengths of light, large quantities of methemoglobin cause erroneous readings in the oxygen saturation reported by conventional pulse oximetry.17 Four local anesthetics have been reported as possible causes of methemoglobinemia—prilocaine, benzocaine, lidocaine, and tetracaine. Of the 242 published episodes of local anesthetic–related methemoglobinemia (from 2000 to 2007; 233 patients with nine repeated episodes), benzocaine (66%) and prilocaine (28%) were the local anesthetics implicated in the greatest number of episodes. Although well tolerated by most patients, the authors recommend against further use of benzocaine and against use of prilocaine in children younger than 6 months of age, pregnant patients, patients receiving other oxidizing drugs, and patients with glucose-6-phosphate dehydrogenase deficiency. Treatment of methemoglobinemia is symptomatic. Treatment consists of administration of oxygen to optimize oxygen delivery to tissues, with respiratory and hemodynamic support as needed, and, when indicated, administration of methylene blue.16
Other Adverse Reactions Other systemic reactions to a local anesthetic include anxiety, vasovagal, anaphylactoid, and anaphylactic reactions. Anxiety can lead to dyspnea, hyperventilation, and other sympathetic responses such as palpitations, hypertension, and tachycardia. A vasovagal episode, with bradycardia, may also occur. In a multicenter dental surgery population, these episodes represented an incidence of 0.5% and were found to be short lived.18 Symptoms consistent with an allergic reaction can often be attributed to the preservative in the local anesthetic product formulation (all multiple dose vials contain a preservative) or the sodium metabisulfite (sulfite, the antioxidant) in an epinephrine-containing formulation. A true immunologic (IgE-mediated) allergic reaction to a local anesthetic is extremely rare. Because the vast majority of reported allergic reactions are to ester local anesthetics (eg, procaine), the amide local anesthetics (lidocaine and bupivacaine) are much more commonly used. The amide local anesthetics are not cross-reactive with ester local anesthetics.19 For patients with a known or suspected local anesthetic allergy, it is best to administer an alternative local anesthetic that is preservative free and without epinephrine.
Conclusion Local anesthetics play an important role in perioperative pain management. Proper patient selection, injection technique, dose, and patient monitoring are important for minimizing the risk of systemic toxicity.
References 1. American Society of Anesthesiologists Task Force on Acute Pain Management. Practice guidelines for acute pain management in the perioperative setting: An updated report by the America Society of Anesthesiologists Task Force on Acute Pain Management. Anesthesiology. 2012;116:248-273. 2. Gordon DB, Dahl JL, Miaskowski C, et al. American Pain Society recommendations for improving the quality of acute and cancer pain management. Arch Intern Med. 2005;165: 1574-1580. 3. Eappen S, Datta S. Pharmacology of local anesthetics. Semin Anesth. 1998;17:10-17. 4. Becker DE, Reed KL. Essentials of local anesthetic pharmacology. Anesth Prog. 2006;53:98-109.
5. Jowza M, Minehart RD. Chapter 15. Local anesthetics. In: Levine WC, ed. Clinical Anesthesia Procedures of the Massachusetts General Hospital, 8th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2010 [Electronically accessed]. 6. Candiotti K, Haas E. Addressing current challenges in managing postsurgical pain with Exparel, a new DepoFoam formulation of bupivacaine. Anesthesiology News. 2012;38:1-8. 7. Chahar P, Cummings KC 3rd. Liposomal bupivacaine: A review of a new bupivacaine formulation. J Pain Res. 2012;5: 257-264. 8. Exparel (Bupivacaine Liposome Injectable Suspension) Product Information. San Diego, CA: Pacira Pharmaceutical Inc.; 2012.
412
9. Neal JM, Bernards CM, Butterworth JF, et al. ASRA practice advisory on local anesthetic systemic toxicity. Reg Anesth Pain Med. 2010;35:152-159. 10. Rosenberg PH, Veering BT, Urmey WF. Maximum recommended doses of local anesthetics: A multifactorial concept. Reg Anesth Pain Med. 2004;29:564-575. 11. Rao RB, Ely SF, Hoffman RS. Deaths related to liposuction. N Engl J Med. 1999;340:1471-1475. 12. Samdal F, Amland PF, Bugge JE. Plasma lidocaine levels during suction-assisted lipectomy using large doses of dilute lidocaine with epinephrine. Plas Reconstr Surg. 1994;93:1217-1223. 13. Lidocaine absorption after topical application during bronchoscopy can lead to problems. ISMP Medication Safety Alert!. 2002; 7. 14. Perrin JH. Hazard of compounded anesthetic gel. Am J Health Syst Pharm. 2005;62:1445-1446.
JULIE GOLEMBIEWSKI 15. Weinberg GL, Ripper R, Murphy P, et al. Lipid infusion accelerates removal of bupivacaine and recovery from bupivacaine toxicity in the isolated rat heart. Reg Anesth Pain Med. 2006;31:296-303. 16. Guay J. Methemoglobinemia related to local anesthetics: A summary of 242 episodes. Anesth Analg. 2009; 108:837-845. 17. Barker SJ, Tremper KK, Hyatt J. Effects of methemoglobinemia on pulse oximetry and mixed venous oximetry. Anesthesiology. 1989;70:112-117. 18. Baluga JC, Casamayou R, Carozzi E, et al. Allergy to local anesthetics in dentistry: Myth or reality? Allergol Immunopathol. 2002;30:14-19. 19. Phillips JF, Yates AB, Deshazo RD. Approach to patients with suspected hypersensitivity to local anesthetics. Am J Med Sci. 2007;334:190-196.
Local Anesthetics Julie Golembiewski, PharmD EFFECTIVE PERIOPERATIVE PAIN MANAGEMENT is important for patient comfort and satisfaction and contributes to improved healing, faster patient mobilization, shorter hospital stays, and lower health care costs.1 Systemic opioids are a mainstay of perioperative pain management, but their use is often associated with adverse effects such as nausea, vomiting, constipation, and pruritus. Whenever possible, a multimodal approach (administration of two or more drugs that act via different mechanisms to provide analgesia) to perioperative pain management should be used to optimize analgesia and minimize opioid adverse events.1,2 For surgical patients, local anesthetics are a key component of a multimodal analgesic regimen. Local anesthetics act by diffusing through the cell membranes and binding to sodium channels to block electrical impulses (action potentials) necessary for nerve conduction. Local anesthetics can be administered by infiltration around the surgical incision site, injected around a peripheral nerve, injected into the epidural space, or injected into the subarachnoid space. Although local anesthetics can be administered topically, this route of administration is generally not used for postoperative pain management.
plasma esterases to their primary metabolite, para-aminobenzoic acid. The amide-type local anesthetics, on the other hand, undergo metabolism in the liver. Local anesthetics vary in their lipid solubility, degree of protein binding, and dissociation constant (pKa). Ropivacaine has greater lipid solubility than lidocaine, allowing a lower milligram dose to achieve a comparable effect (eg, ropivacaine is prepared as a 0.2% or 0.5% solution, whereas lidocaine is prepared as a 1% or 2% solution). Ropivacaine has a high affinity for plasma proteins (94% bound to plasma proteins), prolonging its duration of action compared with lidocaine (55% bound to plasma proteins). The agents with a lower pKa, such as lidocaine and mepivacaine, have a greater portion of molecules in the uncharged (active) form, resulting in a more rapid onset of action than an agent with a higher pKa (eg, ropivacaine).3-5
Novel Formulation of Bupivacaine
Local anesthetics have a lipophilic region and a hydrophilic region linked by either an ester (-CO-) or an amide (-NHC-) bond. The ester-type local anesthetics are quickly hydrolyzed by
Bupivacaine liposome injectable suspension (Exparel; Pacira Pharmaceuticals Inc., San Diego, CA) uses the DepoFoam delivery technology. The liposomes consist of an aqueous bupivacainecontaining core encapsulated by a phospholipid bilayer. The liposomes are nonconcentric, allowing progressive breakdown and reorganization of the lipid bilayer.6,7 This DepoFoam technology extends the delivery of bupivacaine to the site giving the Exparel product a duration of action of 72 hours compared with a duration of action of 2-12 hours for bupivacaine HCl depending on the route of administration.8
Julie Golembiewski, PharmD, is a clinical associate professor, University of Illinois Hospital & Health Sciences, Chicago, IL. Conflict of interest: Julie Golembiewski is a member of a pharmacist advisory board for Pacira Pharmaceuticals, Inc. Address correspondence to Julie Golembiewski, University of Illinois Hospital & Health Sciences System, 1740 West Taylor Street, Suite 3200 (MC 515), Chicago, IL 60612-7239; e-mail address: [email protected]. Ó 2013 by American Society of PeriAnesthesia Nurses 1089-9472/$36.00 http://dx.doi.org/10.1016/j.jopan.2013.09.001
Bupivacaine liposome injectable suspension (Exparel) is infiltrated slowly into the soft tissue layers surrounding the surgical site before closure. The volume (may be diluted with up to 280 mL of saline) varies based on the size of the surgical site, but the maximum dose should not exceed 266 mg (one 20 mL vial of undiluted drug). All the tissue layers (upper portion of subcutaneous tissue, just below the fascia, and just above the fascia) should be slowly injected using a moving needle technique. If aspiration draws blood,
Classification and Pharmacokinetics
Journal of PeriAnesthesia Nursing, Vol 28, No 6 (December), 2013: pp 409-412
409
JULIE GOLEMBIEWSKI
410
the needle is moved to a different location until aspiration is negative. Injecting bupivacaine HCl immediately before Exparel can impact the pharmacokinetic and/or physicochemical properties of Exparel. Injecting lidocaine 20 minutes or less before Exparel or mixing lidocaine with Exparel can cause an immediate release of bupivacaine from Exparel. Other forms of bupivacaine (bupivacaine HCl) should not be administered for 96 hours after the administration of Exparel.8
Local Anesthetic Systemic Toxicity Although serious adverse effects from local anesthetics are rare, central nervous system (CNS) and/or cardiac toxicity from systemic absorption or inadvertent intravascular injection of a local anesthetic can result in disability or death. The likelihood and severity of local anesthetic systemic toxicity (LAST) is affected by the location and type of nerve block, the total dose, patient risk factors, concurrent medications, and timeliness of detection and adequacy of treatment. The classic description of LAST is a progression of symptoms beginning with CNS excitement (eg, auditory changes, metallic taste in the mouth, agitation), followed by seizures, CNS depression (eg, drowsiness, coma), cardiac toxicity (eg, hypertension, tachycardia, arrhythmia) and, ultimately, cardiac depression (eg, bradycardia, asystole, conduction blocks). Case reports, however, describe significant variation to this classic description with many patients experiencing CNS and cardiac toxicity simultaneously or experiencing cardiac toxicity without the initial signs and symptoms of CNS toxicity. The onset of LAST signs and symptoms can be fast (, 5 minutes) if there is inadvertent intravascular injection or slow (.15 minutes) if there is delayed tissue absorption of the local anesthetic.9 The clearance of commonly used local anesthetics (lidocaine, ropivacaine, and bupivacaine) is reduced by extremities of age, renal dysfunction, hepatic dysfunction, and cardiac dysfunction.9,10 Nearly half of the reports of LAST are in patients younger than 16 years of age (16%) or older than 60 years of age (30%). More than one-third of reports of toxicity involved patients with underlying cardiac, neurologic, renal, hepatic, pulmonary, or metabolic disease.9 Dose reduction and heightened vigilance may be warranted in
these patients particularly if they are at the extremes of age.9,10 The maximum recommended dose is intended to prevent an excessive amount of local anesthetic (that could result in toxicity) from being administered. The maximum recommended dose is extrapolated from animal experiments, clinical experiences, measurement of blood concentrations, case reports of toxicity, and pharmacokinetic data.10 Although not perfect, the maximum doses found in textbooks and product information are important guidelines for local anesthetics administered in the perioperative setting. An excessive amount of a local anesthetic can produce toxicity and death even when it is administered subcutaneously or topically. Administration of several liters of very dilute lidocaine with epinephrine during tumescent liposuction has resulted in deaths from lidocaine toxicity or a drug interaction with lidocaine.11 Authors of one study recommend close monitoring of patients for 24 hours after surgery because plasma concentrations of lidocaine continue to rise for 6-12 or more hours after administration.12 High concentrations of lidocaine applied topically to mucous membranes (tracheobronchial tree) or over a large area of skin (especially when an occlusive dressing is used) can also result in lidocaine toxicity (seizure, cardiac arrest, and death).13,14 Treatment of LAST includes prompt and effective airway management, benzodiazepines to suppress seizures, and if cardiac arrest occurs, Advanced Cardiac Life Support with some modifications (10-100 mcg initial epinephrine boluses; avoidance of vasopressin, calcium channel blockers, and beta blockers; and use of amiodarone for ventricular arrhythmias). After airway management, administering 20% lipid emulsion at the first signs of LAST should also be considered.9 Lipid emulsion appears to act as a ‘‘lipid sink’’ to draw the lipidsoluble local anesthetic out from within cardiac tissue, thereby improving cardiac conduction, contractility, and coronary perfusion.15
Methemoglobinemia Local anesthetics are indirect oxidizers of the iron moiety within the hemoglobin molecule, forming methemoglobin that cannot transport oxygen.
PHARMACOLOGY FACTS
411
When methemoglobin concentrations exceed 15% of the circulating hemoglobin, there is less functional hemoglobin to transport oxygen to tissues, and the patient begins to experience symptoms. As the methemoglobin level rises, cyanosis, altered mental status, tachypnea, tachycardia, respiratory compromise (requiring tracheal intubation or tracheotomy), seizures, and coma may occur. The patient’s skin and mucous membranes appear bluish, gray, or pale; chocolate-colored blood suggests methemoglobinemia, although other colors may be found.16 Because the pulse oximeter cannot detect more than two wavelengths of light, large quantities of methemoglobin cause erroneous readings in the oxygen saturation reported by conventional pulse oximetry.17 Four local anesthetics have been reported as possible causes of methemoglobinemia—prilocaine, benzocaine, lidocaine, and tetracaine. Of the 242 published episodes of local anesthetic–related methemoglobinemia (from 2000 to 2007; 233 patients with nine repeated episodes), benzocaine (66%) and prilocaine (28%) were the local anesthetics implicated in the greatest number of episodes. Although well tolerated by most patients, the authors recommend against further use of benzocaine and against use of prilocaine in children younger than 6 months of age, pregnant patients, patients receiving other oxidizing drugs, and patients with glucose-6-phosphate dehydrogenase deficiency. Treatment of methemoglobinemia is symptomatic. Treatment consists of administration of oxygen to optimize oxygen delivery to tissues, with respiratory and hemodynamic support as needed, and, when indicated, administration of methylene blue.16
Other Adverse Reactions Other systemic reactions to a local anesthetic include anxiety, vasovagal, anaphylactoid, and anaphylactic reactions. Anxiety can lead to dyspnea, hyperventilation, and other sympathetic responses such as palpitations, hypertension, and tachycardia. A vasovagal episode, with bradycardia, may also occur. In a multicenter dental surgery population, these episodes represented an incidence of 0.5% and were found to be short lived.18 Symptoms consistent with an allergic reaction can often be attributed to the preservative in the local anesthetic product formulation (all multiple dose vials contain a preservative) or the sodium metabisulfite (sulfite, the antioxidant) in an epinephrine-containing formulation. A true immunologic (IgE-mediated) allergic reaction to a local anesthetic is extremely rare. Because the vast majority of reported allergic reactions are to ester local anesthetics (eg, procaine), the amide local anesthetics (lidocaine and bupivacaine) are much more commonly used. The amide local anesthetics are not cross-reactive with ester local anesthetics.19 For patients with a known or suspected local anesthetic allergy, it is best to administer an alternative local anesthetic that is preservative free and without epinephrine.
Conclusion Local anesthetics play an important role in perioperative pain management. Proper patient selection, injection technique, dose, and patient monitoring are important for minimizing the risk of systemic toxicity.
References 1. American Society of Anesthesiologists Task Force on Acute Pain Management. Practice guidelines for acute pain management in the perioperative setting: An updated report by the America Society of Anesthesiologists Task Force on Acute Pain Management. Anesthesiology. 2012;116:248-273. 2. Gordon DB, Dahl JL, Miaskowski C, et al. American Pain Society recommendations for improving the quality of acute and cancer pain management. Arch Intern Med. 2005;165: 1574-1580. 3. Eappen S, Datta S. Pharmacology of local anesthetics. Semin Anesth. 1998;17:10-17. 4. Becker DE, Reed KL. Essentials of local anesthetic pharmacology. Anesth Prog. 2006;53:98-109.
5. Jowza M, Minehart RD. Chapter 15. Local anesthetics. In: Levine WC, ed. Clinical Anesthesia Procedures of the Massachusetts General Hospital, 8th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2010 [Electronically accessed]. 6. Candiotti K, Haas E. Addressing current challenges in managing postsurgical pain with Exparel, a new DepoFoam formulation of bupivacaine. Anesthesiology News. 2012;38:1-8. 7. Chahar P, Cummings KC 3rd. Liposomal bupivacaine: A review of a new bupivacaine formulation. J Pain Res. 2012;5: 257-264. 8. Exparel (Bupivacaine Liposome Injectable Suspension) Product Information. San Diego, CA: Pacira Pharmaceutical Inc.; 2012.
412
9. Neal JM, Bernards CM, Butterworth JF, et al. ASRA practice advisory on local anesthetic systemic toxicity. Reg Anesth Pain Med. 2010;35:152-159. 10. Rosenberg PH, Veering BT, Urmey WF. Maximum recommended doses of local anesthetics: A multifactorial concept. Reg Anesth Pain Med. 2004;29:564-575. 11. Rao RB, Ely SF, Hoffman RS. Deaths related to liposuction. N Engl J Med. 1999;340:1471-1475. 12. Samdal F, Amland PF, Bugge JE. Plasma lidocaine levels during suction-assisted lipectomy using large doses of dilute lidocaine with epinephrine. Plas Reconstr Surg. 1994;93:1217-1223. 13. Lidocaine absorption after topical application during bronchoscopy can lead to problems. ISMP Medication Safety Alert!. 2002; 7. 14. Perrin JH. Hazard of compounded anesthetic gel. Am J Health Syst Pharm. 2005;62:1445-1446.
JULIE GOLEMBIEWSKI 15. Weinberg GL, Ripper R, Murphy P, et al. Lipid infusion accelerates removal of bupivacaine and recovery from bupivacaine toxicity in the isolated rat heart. Reg Anesth Pain Med. 2006;31:296-303. 16. Guay J. Methemoglobinemia related to local anesthetics: A summary of 242 episodes. Anesth Analg. 2009; 108:837-845. 17. Barker SJ, Tremper KK, Hyatt J. Effects of methemoglobinemia on pulse oximetry and mixed venous oximetry. Anesthesiology. 1989;70:112-117. 18. Baluga JC, Casamayou R, Carozzi E, et al. Allergy to local anesthetics in dentistry: Myth or reality? Allergol Immunopathol. 2002;30:14-19. 19. Phillips JF, Yates AB, Deshazo RD. Approach to patients with suspected hypersensitivity to local anesthetics. Am J Med Sci. 2007;334:190-196.
