AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Deciphering Anesthetic Concentration and Dilution
• Pathophysiology
• Clinical Evaluation
• Differential Diagnosis
• Emergency Treatment
• Disposition
• Medical/Legal Pitfalls
• Acknowledgments
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Deciphering Anesthetic Concentration and Dilution
• Pathophysiology
• Clinical Evaluation
• Differential Diagnosis
• Emergency Treatment
• Disposition
• Medical/Legal Pitfalls
• Acknowledgments
• References

The need to perform painful procedures in the emergency department (ED) makes the use of local and infiltration anesthesia necessary components of patient care. While generally safe, anesthetic agents can be toxic if used in inappropriate doses or route. Even when properly administered, patients may experience unintended reactions to local anesthetics. The manifestations of toxicity associated with local anesthetic agents used in the ED and treatment strategies are discussed in this article. 

For a related CME activity, see CME/CE - Topical Anesthetics in Children.

Physiochemical variables 

Local anesthetics can be divided into 2 groups: the esters and the amides. Onset of action, potency, and duration of action are determined by the specific local anesthetic’s pKa, lipid solubility, protein binding, tissue pH, and vasodilatory effects. Increasing the dose by administering a high concentration shortens onset, while increasing potency and duration of action, as well as increasing possibility for the adverse/toxic reactions. Other factors that affect onset, potency, and duration are described below. 

• Onset of action
• • pKa is the primary factor that determines onset of action.
  • Lower pKa increases tissue penetration and shortens onset of action; this is due to increased lipid solubility of nonionized (uncharged) particles.
  • pKa that is closer to pH optimizes penetration.
  • Inflammation in the extracellular space may decrease pH and may slow onset of action.
  • Site of administration influences onset (ie, prolonged in areas with increased tissue or nerve sheath size).
• Potency
• • Local anesthetics with high partition coefficients that increase lipophilic properties easily pass into the lipid nerve membrane.
  • Degree of vasodilation promotes vascular absorption, thereby reducing locally available drug and decreases potency.
  • Addition of epinephrine or sodium bicarbonate increases pH, thereby increasing nonionized particles, which are more lipid soluble.
  • Generally, local anesthetic solutions that contain premixed epinephrine contain preservatives; in these solutions, the pH is adjusted lower to maintain the stability of epinephrine and antioxidants.
• Duration of action
• • Addition of epinephrine to some local anesthetic solutions prolongs duration of action by causing vasoconstriction and decreasing systemic absorption.
  • Degree of protein binding primarily determines duration of action; high protein binding increases duration.
  • Increasing pH (addition of epinephrine or sodium bicarbonate) also prolongs duration of action. 

Table 1. Local Anesthetic Agents Used Commonly for Infiltrative Injection

Further clinical trials in the 1990s led to the introduction in 1996 of ropivacaine, a pure S-(-) enantiomer. Ropivacaine, like bupivacaine, has the capacity to produce differential blockade but has a better sensorimotor dissociation at lower doses. This long-acting amide is the first local anesthetic drug developed with initial extensive toxicological studies before its clinical release. Although ropivacaine may be associated with acute CNS and cardiovascular toxicity, the incidence appears to be rare.

Dosage guidelines

Lower concentrations of local anesthetics are typically used for infiltration anesthesia.

Variation in local anesthetic dose is dependent on the procedure, the degree of anesthesia required, and individual patient circumstances.

Reduced dosage is indicated in debilitated or acutely ill patients; in very young children or geriatric patients; and in patients with liver disease, arteriosclerosis, or occlusive arterial disease.  

Administrative techniques

Infiltration anesthesia is accomplished by administering the local anesthetic solution intradermally (ID), subcutaneously (SC), or submucosally across the nerve path supplying the area of the body requiring anesthesia. See Local Anesthetic Agents, Infiltrative Administration.

A common administrative technique is to subcutaneously inject the local anesthetic in a circular pattern around the operative site; this circular patterned administration is often referred to as field block technique.

DECIPHERING ANESTHETIC CONCENTRATION AND DILUTION

Section 3 of 11  

• Authors and Editors
• Introduction
• Deciphering Anesthetic Concentration and Dilution
• Pathophysiology
• Clinical Evaluation
• Differential Diagnosis
• Emergency Treatment
• Disposition
• Medical/Legal Pitfalls
• Acknowledgments
• References

Concentration 

Drug concentration is expressed as a percentage (eg, bupivacaine 0.25%, lidocaine 1%).

• Percentage is measured in grams per 100 mL (ie, 1% is 1 g/100 mL [1000 mg/100 mL], or 10 mg per mL).
• Calculate the mg/mL concentration quickly from the percentage by moving the decimal point 1 place to the right (see examples below).
• • Bupivacaine 0.25% = 2.5 mg/mL
  • Lidocaine 1% = 10 mg/mL

Dilution 

When epinephrine is combined in an anesthetic solution, the result is expressed as a dilution (eg, 1:100,000). 

• 1:1000 means 1 mg per 1 mL (ie, 0.1%)
• 1:10,000 means 1 mg per 10 mL (ie, 0.01%)
• 1:2000 means 1 mg per 2 mL (ie, 0.05%)
• 1:20,000 means 1 mg per 20 mL (ie, 0.005%)
• 0.1 mL of 1:1000 epinephrine added to 10 mL of anesthetic solution = 1:100,000 dilution or 0.01 mg/mL

PATHOPHYSIOLOGY

Section 4 of 11  

• Authors and Editors
• Introduction
• Deciphering Anesthetic Concentration and Dilution
• Pathophysiology
• Clinical Evaluation
• Differential Diagnosis
• Emergency Treatment
• Disposition
• Medical/Legal Pitfalls
• Acknowledgments
• References

The toxicity of local and infiltration anesthetics can be classified by local and systemic levels of manifestations. The local adverse effects of anesthetic agents include neurovascular manifestations such as prolonged anesthesia and paresthesias, which may become irreversible.

Systemic toxicity of anesthetics involves the central nervous system (CNS), the cardiovascular system, and the immune system. In relatively rare instances (<1%), the effects on the immune system can produce immunoglobulin E (IgE)–mediated allergic reaction. Most cases are associated with the use of amino esters. Some anesthetics, particularly benzocaine, is associated with hematologic effects, namely methemoglobinemia. Cardiovascular effects are primarily those of direct myocardial depression and bradycardia, which may lead to cardiovascular collapse.

Note that toxicity of anesthetics may be potentiated in patients with renal or hepatic compromise, respiratory acidosis, preexisting heart block, or heart conditions. Toxicity may be potentiated during pregnancy, at the extremes of age, or in those with hypoxia. However, inadvertent intravascular injection is the most common cause of local anesthetic toxicity even if anesthetic was administered within the recommended dose range.

In the following table, the minimum doses of anesthetics in which adverse reactions have occurred are listed.

Table 3. Minimum Intravenous Toxic Dose of Local Anesthetic in Humans¹

CLINICAL EVALUATION

Section 5 of 11  

• Authors and Editors
• Introduction
• Deciphering Anesthetic Concentration and Dilution
• Pathophysiology
• Clinical Evaluation
• Differential Diagnosis
• Emergency Treatment
• Disposition
• Medical/Legal Pitfalls
• Acknowledgments
• References

After the use of local anesthetic agents, consider new signs or symptoms as a possible sign of toxicity when evaluating patients in the ED. The manifestation of toxicity depends on the organ system or systems that are affected. Below is a list of toxicity manifestations organized by the affected organ system.

Central nervous system signs

• Initial symptoms
• • Lightheadedness
  • Dizziness
  • Visual and auditory disturbances (difficulty focusing and tinnitus)
  • Disorientation
  • Drowsiness
• Higher-dose symptoms
• • Often occur after an initial CNS excitation followed by a rapid CNS depression
  • Muscle twitching
  • Convulsions
  • Unconsciousness
  • Coma
  • Respiratory depression and arrest
  • Cardiovascular depression and collapse

• Direct cardiac effects
• • Toxic doses of local anesthetic agents can cause myocardial depression (tetracaine, etidocaine, bupivacaine), cardiac dysrhythmias (bupivacaine), and cardiotoxicity in pregnancy.
  • Several anesthetics also have negative inotropic effects on cardiac muscle that lead to hypotension. Bupivacaine is especially cardiotoxic.
• Peripheral effects
• • Vasoconstriction at low doses
  • Vasodilatation at higher doses (hypotension)
• The range of signs and symptoms of cardiovascular toxicity include the following:
• • Chest pain
  • Shortness of breath
  • Palpitations
  • Lightheadedness
  • Diaphoresis
  • Hypotension
  • Syncope

Methemoglobinemia has been frequently reported in association with benzocaine use; however, lidocaine and prilocaine have also been implicated. O-toluidine, the liver metabolite of prilocaine, is a potent oxidizer of hemoglobin to methemoglobin. At low levels (1-3%), methemoglobinemia can be asymptomatic, but higher levels (10-40%) may be accompanied by any of the following complaints:

• Cyanosis
• Cutaneous discoloration (gray)
• Tachypnea
• Dyspnea
• Exercise intolerance
• Fatigue
• Dizziness and syncope
• Weakness

Amino esters are derivatives of para-aminobenzoic acid (PABA), which have been associated with acute allergic reactions. Previous studies indicate a 30% rate of allergic reactions to procaine, tetracaine, and chloroprocaine. Amino amides are not associated with PABA and do not produce allergic reactions with the same frequency. However, preparations of amide anesthetics may sometimes contain methylparaben, which is structurally similar to PABA and, thus, may result in allergic reactions.
 
Allergic manifestations of local anesthetics include rash and urticaria. Anaphylaxis due to local anesthetics is very rare but should be considered if the patient is wheezing or in respiratory distress following administration. Patients who report an allergy to lidocaine are likely allergic to the methylparaben preservative. Preservative-free lidocaine can be obtained from individual ampules of lidocaine or from preservative-free lidocaine used by cardiologists and anesthesiologists.

Local tissue manifestations

In addition to numbness and paresthesias, which is expected in the normal range of local anesthetic application, very high doses of local anesthetics can produce irreversible conduction block within 5 minutes. Peripheral neurotoxicity, such as prolonged sensory and motor deficits, has also been documented. It is hypothesized that a combination of low pH and sodium bisulfite in the mixture can be partially responsible for these changes. Reversible skeletal muscle damage has also been reported.

Topical application

A variety of anesthetics are available for topical or mucosal application (eg, tetracaine, benzocaine, lidocaine), and adverse effects are usually caused by high plasma concentrations of the local anesthetic resulting from excessive exposure. Typically, this is caused by application to abraded or torn skin. The following adverse effects may occur: 

• Local burning or stinging may occur.
• Oral viscous lidocaine may cause systemic toxicity, particularly with repeated use in infants or children.
• CNS
• • High plasma concentration initially produces CNS stimulation (including seizures), followed by CNS depression (including respiratory arrest); CNS stimulatory effects may be absent in some patients, particularly when amides (eg, tetracaine) are administered.
  • Epinephrine-containing solutions may add to the CNS stimulatory effect.
• Cardiovascular
• • High plasma levels typically depress the heart and may include bradycardia, dysrhythmias, hypotension, cardiovascular collapse, and cardiac arrest
  • Epinephrine-containing local anesthetics may cause hypertension, tachycardia, and myocardial ischemia.
• Gag-reflex suppression with oral administration
• Other adverse effects include the following:
• • Transient burning sensation
  • Skin discoloration
  • Swelling
  • Neuritis
  • Tissue necrosis and sloughing
  • Methemoglobinemia with prilocaine  

For more information on topical anesthetics, see Anesthesia, Topical.

Warnings regarding cocaine as a topical anesthetic 

A variety of anesthetic mixtures containing cocaine have been used to anesthetize minor skin lacerations, especially on the face or scalp. One such combination that is extemporaneously prepared by hospital pharmacies includes tetracaine 0.5%, epinephrine (adrenaline) 1:2000, and cocaine 11.8% (commonly referred to as "TAC" solution). Use results in decreased pain on application and may provide better patient tolerance of the suturing, particularly in those unable to tolerate injections or those who have difficulty following instructions or sitting still (eg, children, mentally challenged individuals). However, serious toxic effects (eg, seizures, cardiac death) have been described after topical cocaine application, particularly in infants and children. Because of this, cocaine is no longer recommended for topical anesthesia due to increased toxicity, expense, and federal regulatory issues. 

Newer compounded mixtures have replaced cocaine with lidocaine 4% (LET solutions) because of its superior safety when applied to injured skin. Still, these solutions should not be applied to wounds with end arteriolar blood supply.

For more information on cocaine as a topical anesthetic, see Topical Anesthetics, Cocaine.

DIFFERENTIAL DIAGNOSIS

Section 6 of 11  

• Authors and Editors
• Introduction
• Deciphering Anesthetic Concentration and Dilution
• Pathophysiology
• Clinical Evaluation
• Differential Diagnosis
• Emergency Treatment
• Disposition
• Medical/Legal Pitfalls
• Acknowledgments
• References

Anaphylaxis

Bradydysrhythmias

Methemoglobinemia

Seizures

Tachydysrhythmias

EMERGENCY TREATMENT

Section 7 of 11  

• Authors and Editors
• Introduction
• Deciphering Anesthetic Concentration and Dilution
• Pathophysiology
• Clinical Evaluation
• Differential Diagnosis
• Emergency Treatment
• Disposition
• Medical/Legal Pitfalls
• Acknowledgments
• References

In the patient with suspected local anesthetic toxicity, the initial step is stabilization of potential life threats. Impending airway compromise, significant hypotension, and treatment of dysrhythmias and seizures take precedence. Once other possible etiologies of the patient's new symptoms have been excluded, management of the specific symptoms can begin.

Although allergic reactions to local anesthetics are extremely rare, these are treated according to severity. Mild cutaneous reactions may be treated with diphenhydramine (Benadryl 25-50 mg IV/PO for adult doses, 1 mg/kg for pediatric doses); treat patients with more serious reactions with 0.3 (mL) of epinephrine SC (1:1000), and closely monitor for further decompensation. Corticosteroids (125 mg methylprednisolone IVP, or 60 mg prednisone PO) should be given to the patient with severe allergic reactions (eg, respiratory distress, hypotension).

Treatment of CNS complications and toxicity is still very controversial because no single remedy exists. CNS manifestations, such as seizures, have been treated successfully with benzodiazepines and barbiturates (eg, phenobarbital). Recent reports indicate that 1 mg/kg of intravenous propofol (Diprivan) and 2 mg/kg of intravenous thiopental (Pentothal) are successful in stopping local anesthetic-induced seizures and muscle twitching. Clinicians should be aware that propofol can by itself cause significant bradycardia that can further compromise the cardiovascular status of the patient. Avoid use of phenytoin (Dilantin) because it shares pharmacologic properties (ie, sodium channel blockade) with lidocaine and may potentiate toxicity.

Prolonged PR, QRS, and QT intervals potentiating reentrant tachycardias with aberrant conduction may herald cardiovascular toxicity. Expect that cardiac resuscitation of such patients may be difficult and prolonged (30-45 min) because some anesthetics are very lipid soluble and require a long time for redistribution. However, most cases of lidocaine-induced cardiac toxicity can be successfully treated with properly conducted cardiopulmonary resuscitation (CPR) (airway protection and chest compression) due to its relatively short duration of action.

In the setting of anesthetic toxicity, avoiding the use of class IB antidysrhythmic agents, such as phenytoin, mexiletine (Mexitil), and tocainide (Tonocard), is crucial because they may worsen toxicity. Bupivacaine depresses conduction and contractility at low doses. Lidocaine has been used successfully in bupivacaine-induced dysrhythmias, but its additive CNS toxicity is still a major concern. Even though bretylium theoretically should not potentiate CNS toxicity (as does lidocaine), its benefits in cardiovascular resuscitation are unclear. Evidence for use of amiodarone is also lacking at this time. A study performed in a porcine model shows that CPR with a combination of vasopressin and epinephrine resulted in significantly better survival rates than either drug alone.² Human data are currently lacking. Lastly, some recent case reports have indicated that the use of cardiac pacing and cardiopulmonary bypass may improve the outcome in the setting of prolonged resuscitation.¹

In a Korean study, combined boluses of glucose, insulin, and potassium were successful in reversing bupivacaine-induced cardiovascular collapse.³ However, the 2 units/kg dose of insulin used in this protocol may be challenging to use in clinical practice because of physicians' reluctance to administer such unusually high doses of insulin. In China, shenfu, an extract of traditional Chinese herbal medicines, was shown to reduce the CNS and cardiovascular toxicity of bupivacaine on rats.⁴

In cases of refractory cardiovascular collapse caused by an overwhelming overdose of local anesthetic, Weinberg et al (1998 and 2003) demonstrated the successful application of lipid emulsion infusion in the resuscitation of bupivacaine-induced cardiac arrest.^{5, 6} The proposed mechanism is that lipid infusion accelerates the decline in bupivacaine myocardial content (reduced tissue binding) by creating a lipid phase that extracts the lipid-soluble bupivacaine molecules from the aqueous plasma phase. A beneficial energetic-metabolic effect may also occur. 

To date, 3 successful case reports have been documented in humans with the use of lipid infusion in significant local anesthetic toxicity. Rosenblatt and colleagues (2006) were the first to report use of a 20% lipid infusion to resuscitate a patient from prolonged cardiac arrest that followed an interscalene block with bupivacaine and mepivacaine.⁷ Litz and colleagues (2006) published a case report after ropivacaine-induced asystole.⁸ Foxall and colleagues (2007) successfully treated levobupivacaine-induced seizures and cardiovascular collapse.⁹ This last case was the first one to demonstrate efficacy of lipid emulsion in a peri-arrest situation.

Weinberg's recommended dosing regimen for use in humans

In cardiac arrest secondary to local anesthetic toxicity that is unresponsive to standard therapy, intravenous administration of a lipid such as Intralipid 20% is recommended in the following regimen: 

1. Administer 1 mL/kg over 1 minute.
2. Repeat twice more at 3– to 5-minute intervals.
3. Then (or sooner if stability is restored), convert to an infusion at a rate of 0.25 mL/kg/min, continuing until hemodynamic stability is restored.
4. Increasing the dose beyond 8 mL/kg is unlikely to be useful.
5. In practice, resuscitate an adult weighing 70 kg as follows:
6. 1. Use a 500-mL bag of fat emulsion (Intralipid 20%) and a 50-mL syringe.
   2. Draw up 50 mL and give it stat intravenously, and then draw up and give another 20 mL.
   3. Do exactly the same thing up to twice more as the epinephrine is given—if necessary or appropriate.
   4. Then, attach the fat emulsion bag to a giving set and administer it intravenously over the next 15 minutes.

Note that propofol (Diprivan) is not a component of lipid rescue. It is formulated in a 10% lipid emulsion and therefore an overdose of propofol (gram quantities) would be necessary to provide an adequate dose of lipid emulsion. Propofol is contraindicated when there is any evidence of cardiovascular toxicity.

In esse
 
Local ischemic or nerve toxicities may occur, particularly in the extremities with prolonged anesthesia or epinephrine use. Suspected nerve damage should prompt neurologic consultation for urgent peripheral nerve studies. If vascular compromise, such as limb ischemia, is suspected, consult a vascular surgeon immediately. Therapy for extravasation (eg, warm compresses, phentolamine, nitroglycerin cream) should be initiated for localized vascular toxicity. 

Methemoglobinemia should initially be treated symptomatically and then guided by blood levels of methemoglobin. Methylene blue and hyperbaric oxygen may be required in severe cases. See Methemoglobinemia for specific treatment.

DISPOSITION

Section 8 of 11  

• Authors and Editors
• Introduction
• Deciphering Anesthetic Concentration and Dilution
• Pathophysiology
• Clinical Evaluation
• Differential Diagnosis
• Emergency Treatment
• Disposition
• Medical/Legal Pitfalls
• Acknowledgments
• References

Patients with persistent or unresolved significant reactions require admission to a monitored bed for observation, further evaluation, and treatment. Patients who are stable and have minor or easily controlled adverse reactions can be discharged and monitored on an outpatient basis. Advise patients with adverse reactions to avoid the specific anesthetic agent in the future and to alert medical personnel of the reaction.

If a patient has experienced an adverse reaction to one class of anesthetic (ester or amide), risk for adverse reactions is higher for all agents in that class.

MEDICAL/LEGAL PITFALLS

Section 9 of 11  

• Authors and Editors
• Introduction
• Deciphering Anesthetic Concentration and Dilution
• Pathophysiology
• Clinical Evaluation
• Differential Diagnosis
• Emergency Treatment
• Disposition
• Medical/Legal Pitfalls
• Acknowledgments
• References

The following are suggestions that may help avoid complications related to local anesthetic use in the ED:

• Consider obtaining and documenting informed consent in individuals with a prior history of anesthetic reactions.
• Document amount and type of anesthetic used during the procedure.
• Always obtain an adequate history and physical examination to identify risk factors and allergies.
• Do not use class IB antidysrhythmics (including phenytoin) for seizures or dysrhythmias believed to be due to cocaine toxicity.
• Consider changes in signs or symptoms as a possible manifestation of anesthetic toxicity.
• Admit patients with serious or unresolved symptoms.

ACKNOWLEDGMENTS

Section 10 of 11  

• Authors and Editors
• Introduction
• Deciphering Anesthetic Concentration and Dilution
• Pathophysiology
• Clinical Evaluation
• Differential Diagnosis
• Emergency Treatment
• Disposition
• Medical/Legal Pitfalls
• Acknowledgments
• References

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author, Bret Ginther, MD, to the development and writing of this article.

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Deciphering Anesthetic Concentration and Dilution
• Pathophysiology
• Clinical Evaluation
• Differential Diagnosis
• Emergency Treatment
• Disposition
• Medical/Legal Pitfalls
• Acknowledgments
• References

1. Goldfrank LR, Flomenbaum NE, Lewin NA, et al. Goldfrank's Toxicologic Emergencies. 1507-17. 6^th ed. New York: McGraw-Hill; 1998:897-903.
2. Mayr VD, Raedler C, Wenzel V, Lindner KH, Strohmenger HU. A comparison of epinephrine and vasopressin in a porcine model of cardiac arrest after rapid intravenous injection of bupivacaine. Anesth Analg. May 2004;98(5):1426-31, table of contents. [Medline].
3. Kim JT, Jung CW, Lee KH. The effect of insulin on the resuscitation of bupivacaine-induced severe cardiovascular toxicity in dogs. Anesth Analg. Sep 2004;99(3):728-33, table of contents. [Medline].
4. Wang Q, Liu Y, Lei Y, Yang J, Chen S, Chen M, et al. Shenfu injection reduces toxicity of bupivacaine in rats. Chin Med J (Engl). Sep 2003;116(9):1382-5. [Medline].
5. Weinberg GL, VadeBoncouer T, Ramaraju GA, Garcia-Amaro MF, Cwik MJ. Pretreatment or resuscitation with a lipid infusion shifts the dose-response to bupivacaine-induced asystole in rats. Anesthesiology. Apr 1998;88(4):1071-5. [Medline].
6. Weinberg GL, Ripper R, Feinstein DL, Hoffman W. Lipid emulsion infusion rescues dogs from bupivacaine-induced cardiac toxicity. Reg Anesth Pain Med. May-Jun 2003;28(3):198-202. [Medline].
7. Rosenblatt MA, Abel M, Fischer GW, Itzkovich CJ, Eisenkraft JB. Successful use of a 20% lipid emulsion to resuscitate a patient after a presumed bupivacaine-related cardiac arrest. Anesthesiology. Jul 2006;105(1):217-8. [Medline].
8. Litz RJ, Popp M, Stehr SN, Koch T. Successful resuscitation of a patient with ropivacaine-induced asystole after axillary plexus block using lipid infusion. Anaesthesia. Aug 2006;61(8):800-1. [Medline].
9. Foxall G, McCahon R, Lamb J, Hardman JG, Bedforth NM. Levobupivacaine-induced seizures and cardiovascular collapse treated with Intralipid. Anaesthesia. May 2007;62(5):516-8. [Medline].
10. Achar S, Kundu S. Principles of office anesthesia: part I. Infiltrative anesthesia. Am Fam Physician. Jul 1 2002;66(1):91-4. [Medline].
11. Arky R. Physician's Desk Reference. ed. Medical Economics Data; 1996.
12. Chen AH. Toxicity and allergy to local anesthesia. J Calif Dent Assoc. Sep 1998;26(9):683-92. [Medline].
13. Hogan Q. Local anesthetic toxicity: an update. Reg Anesth. 21(6 Suppl):43-50. [Medline].
14. Katzung BG. Basic and Clinical Pharmacology. 6^th ed. New York: McGraw-Hill; 1995:395-403.
15. McGee D. Local and topical anesthesia. In: Roberts JR, Hedges J, eds. Clinical Procedures in Emergency Medicine. 4^th ed. Philadelphia, Pa: WB Saunders; 2004:533-551.
16. Miller RD, Cucchiara RF, Miller ED, et al. Anesthesia. 4^th ed. Chronicle Books; 1994:489-521.
17. Picard J, Meek T. Lipid emulsion to treat overdose of local anaesthetic: the gift of the glob. Anaesthesia. Feb 2006;61(2):107-9. [Medline].
18. Ruetsch YA, Boni T, Borgeat A. From cocaine to ropivacaine: the history of local anesthetic drugs. Curr Top Med Chem. Aug 2001;1(3):175-82. [Medline].

Article Last Updated: Mar 18, 2008