Close
New

Medscape is available in 5 Language Editions – Choose your Edition here.

 

Local Anesthetic Toxicity Clinical Presentation

  • Author: Raffi Kapitanyan, MD; Chief Editor: Asim Tarabar, MD  more...
 
Updated: Apr 30, 2016
 

History

Manifestations of local anesthetic toxicity typically appear 1-5 minutes after the injection, but onset may range from 30 seconds to as long as 60 minutes.[1] Initial manifestations may also vary widely. Classically, patients experience symptoms of central nervous system (CNS) excitement such as the following:

  • Circumoral and/or tongue numbness
  • Metallic taste
  • Lightheadedness
  • Dizziness
  • Visual and auditory disturbances (difficulty focusing and tinnitus)
  • Disorientation
  • Drowsiness

Although cardiac toxicity classically does not occur without preceding CNS toxicity, numerous published case reports describe episodes limited to cardiovascular manifestations. In these cases, onset of symptoms was delayed by 5 minutes or more.[1]

Next

Physical Examination

After the use of local anesthetic agents, consider the appearance of new signs or symptoms as a possible sign of toxicity. The manifestation of toxicity depends on the organ system or systems that are affected. Toxicity manifestations can be categorized as follows:

  • CNS
  • Cardiovascular
  • Hematologic
  • Allergic
  • Local tissue

Central nervous system manifestations

With higher doses, initial CNS excitation is often followed by a rapid CNS depression, with the following features:

  • Muscle twitching
  • Convulsions
  • Unconsciousness
  • Coma
  • Respiratory depression and arrest
  • Cardiovascular depression and collapse

With progression of toxicity, the patient may experience tonic-clonic seizures and, eventually, unconsciousness and coma. CNS symptoms may be masked in patients premedicated with anticonvulsants such as benzodiazepines or barbiturates. The first sign of toxicity in these premedicated patients may be cardiovascular depression.

When blood levels are high enough to block inhibitory and excitatory pathways, convulsions cease and the patient may experience respiratory depression or arrest and cardiovascular depression. Large bolus injections may increase peak anesthetic levels to the point where the CNS and cardiovascular system are affected simultaneously.

Cardiovascular manifestations

Risk of cardiovascular toxicity is somewhat greater with lipophilic local anesthetics such as bupivacaine. Risk of cardiac toxicity is greatest in those patients with underlying cardiac conduction problems or after myocardial infarction.

Toxic doses of local anesthetic agents can cause myocardial depression (tetracaine, etidocaine, bupivacaine), cardiac dysrhythmias (bupivacaine), and cardiotoxicity in pregnancy. Several anesthetics (eg, lidocaine) also alter vascular tone, with low doses having vasoconstrictive effects and higher doses causing relaxation of vascular smooth muscle, possibly leading to hypotension.

The range of signs and symptoms of cardiovascular toxicity include the following:

  • Chest pain
  • Shortness of breath
  • Palpitations
  • Lightheadedness
  • Diaphoresis
  • Hypotension
  • Syncope

Effects on cardiac conduction include widened PR interval, widened QRS duration, sinus tachycardia, sinus arrest, and partial or complete atrioventricular dissociation. Cardiac arrest has been reported after intraurethral administration of lidocaine.[4]

Cardiac toxicity is potentiated by acidosis, hypercapnia, and hypoxia, which worsen cardiac suppression and increase the chance of arrhythmia. This is important to consider since seizure makes this metabolic picture more likely.

Hematologic manifestations

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

Allergic manifestations

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 starts to wheeze or suffer respiratory distress after receiving the anesthetic. 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 with normal doses of local anesthetic, very high doses 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.

Adverse effects of topical application

A variety of anesthetics are available for topical or mucosal application (eg, tetracaine, benzocaine, lidocaine). Adverse effects from these agents typically occur when they are applied to abraded or torn skin, resulting in systemic absorption and high plasma concentrations of the agent. Similarly, absorption of oral viscous lidocaine may cause systemic toxicity, particularly with repeated use in infants or children.

The following systemic reactions may occur with topical anesthetics:

  • 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 with amides (eg, tetracaine); epinephrine-containing solutions may add to the CNS stimulatory effect
  • Cardiovascular: High plasma levels typically depress the heart; effects may include bradycardia, dysrhythmias, hypotension, cardiovascular collapse, and cardiac arrest; epinephrine-containing local anesthetics may cause hypertension, tachycardia, and myocardial ischemia
  • Suppression of the gag reflex with oral administration

Other adverse effects include the following:

  • Transient local burning or stinging sensation
  • Skin discoloration
  • Swelling
  • Neuritis
  • Tissue necrosis and sloughing
  • Methemoglobinemia with prilocaine

For more information on topical anesthetics, see Topical Anesthesia.

Adverse effects of cocaine as a topical anesthetic

Various anesthetic mixtures containing cocaine have been used to provide topical anesthesia for suturing of 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). TAC is particularly useful in patients who are unable to tolerate injections or 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 toxicity, as well as expense and federal regulatory issues, cocaine is no longer recommended for topical anesthesia.

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

Previous
 
 
Contributor Information and Disclosures
Author

Raffi Kapitanyan, MD Assistant Professor of Emergency Medicine, Rutgers Robert Wood Johnson Medical School

Raffi Kapitanyan, MD is a member of the following medical societies: American College of Emergency Physicians, Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Coauthor(s)

Mark Su, MD, MPH, FACEP, FACMT Consulting Staff and Director of Fellowship in Medical Toxicology, Department of Emergency Medicine, North Shore University Hospital

Mark Su, MD, MPH, FACEP, FACMT is a member of the following medical societies: American Academy of Clinical Toxicology, American College of Emergency Physicians, American College of Medical Toxicology, Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Chief Editor

Asim Tarabar, MD Assistant Professor, Director, Medical Toxicology, Department of Emergency Medicine, Yale University School of Medicine; Consulting Staff, Department of Emergency Medicine, Yale-New Haven Hospital

Disclosure: Nothing to disclose.

Acknowledgements

John G Benitez, MD, MPH Associate Professor, Department of Medicine, Medical Toxicology, Vanderbilt University Medical Center; Managing Director, Tennessee Poison Center

John G Benitez, MD, MPH is a member of the following medical societies: American Academy of Clinical Toxicology, American Academy of Emergency Medicine, American College of Medical Toxicology, American College of Preventive Medicine, Society for Academic Emergency Medicine, Undersea and Hyperbaric Medical Society, and Wilderness Medical Society

Disclosure: Nothing to disclose.

Russell F Kelly MD, Assistant Professor, Department of Internal Medicine, Rush Medical College; Chairman of Adult Cardiology and Director of the Fellowship Program, Cook County Hospital

Russell F Kelly is a member of the following medical societies: American College of Cardiology

Disclosure: Nothing to disclose.

Lance W Kreplick, MD, FAAEM, MMM Medical Director of Hyperbaric Medicine, Fawcett Wound Management and Hyperbaric Medicine; Consulting Staff in Occupational Health and Rehabilitation, Company Care Occupational Health Services; President and Chief Executive Officer, QED Medical Solutions, LLC

Lance W Kreplick, MD, FAAEM, MMM, is a member of the following medical societies: American Academy of Emergency Medicine and American College of Physician Executives

Disclosure: Nothing to disclose.

Harold L Manning, MD Professor, Departments of Medicine, Anesthesiology and Physiology, Section of Pulmonary and Critical Care Medicine, Dartmouth Medical School

Harold L Manning, MD is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, and American Thoracic Society

Disclosure: Nothing to disclose.

Ruben Peralta, MD, FACS Professor of Surgery, Anesthesia and Emergency Medicine, Senior Medical Advisor, Board of Directors, Program Chief of Trauma, Emergency and Critical Care, Consulting Staff, Professor Juan Bosch Trauma Hospital, Dominican Republic

Ruben Peralta, MD, FACS is a member of the following medical societies: American Association of Blood Banks, American College of Healthcare Executives, American College of Surgeons, American Medical Association, Association for Academic Surgery, Eastern Association for the Surgery of Trauma, Massachusetts Medical Society, Society of Critical Care Medicine, and Society of Laparoendoscopic Surgeons

Disclosure: Nothing to disclose.

Michael R Pinsky, MD, CM, FCCP, FCCM Professor of Critical Care Medicine, Bioengineering, Cardiovascular Disease and Anesthesiology, Vice-Chair of Academic Affairs, Department of Critical Care Medicine, University of Pittsburgh Medical Center, University of Pittsburgh School of Medicine

Michael R Pinsky, MD, CM, FCCP, FCCM is a member of the following medical societies: American College of Chest Physicians, American College of Critical Care Medicine, American Heart Association, American Thoracic Society, Association of University Anesthetists, European Society of Intensive Care Medicine, Shock Society, and Society of Critical Care Medicine

Disclosure: LiDCO Ltd Honoraria Consulting; iNTELOMED Intellectual property rights Board membership; Edwards Lifesciences Honoraria Consulting

Karl A Poterack, MD Consulting Staff, Department of Anesthesiology, Mayo Clinic Scottsdale

Karl A Poterack, MD is a member of the following medical societies: American Society of Anesthesiologists

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

References
  1. [Guideline] Neal JM, Mulroy MF, Weinberg GL. American Society of Regional Anesthesia and Pain Medicine checklist for managing local anesthetic systemic toxicity: 2012 version. Reg Anesth Pain Med. 2012 Jan-Feb. 37(1):16-8. [Medline]. [Full Text].

  2. Schwartz DR, Kaufman B. Local Anesthetics. In: Hoffman RS, Howland MA, Lewin NA, Nelson LS, Goldfrank LR, eds. Goldfrank's Toxicologic Emergencies. 10th ed. New York: McGraw-Hill Education; 2015.

  3. Mowry JB, Spyker DA, Brooks DE, McMillan N, Schauben JL. 2014 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 32nd Annual Report. Clin Toxicol (Phila). 2015. 53 (10):962-1147. [Medline]. [Full Text].

  4. Chang YY, Ho CM, Tsai SK. Cardiac arrest after intraurethral administration of lidocaine. J Formos Med Assoc. 2005 Aug. 104(8):605-6. [Medline].

  5. Soltesz EG, van Pelt F, Byrne JG. Emergent cardiopulmonary bypass for bupivacaine cardiotoxicity. J Cardiothorac Vasc Anesth. 2003 Jun. 17(3):357-8. [Medline].

  6. [Guideline] The Association of Anaesthetists of Great Britain and Ireland. Guidelines for the Management of Severe Local Anaesthetic Toxicity. 2010. [Full Text].

  7. Leskiw U, Weinberg GL. Lipid resuscitation for local anesthetic toxicity: is it really lifesaving?. Curr Opin Anaesthesiol. 2009 Oct. 22(5):667-71. [Medline].

  8. Kim JT, Jung CW, Lee KH. The effect of insulin on the resuscitation of bupivacaine-induced severe cardiovascular toxicity in dogs. Anesth Analg. 2004 Sep. 99(3):728-33, table of contents. [Medline].

  9. Wang Q, Liu Y, Lei Y, et al. Shenfu injection reduces toxicity of bupivacaine in rats. Chin Med J (Engl). 2003 Sep. 116(9):1382-5. [Medline].

  10. Weinberg GL. Lipid infusion therapy: translation to clinical practice. Anesth Analg. 2008 May. 106(5):1340-2. [Medline]. [Full Text].

  11. Mazoit JX, Le Guen R, Beloeil H, Benhamou D. Binding of long-lasting local anesthetics to lipid emulsions. Anesthesiology. 2009 Feb. 110(2):380-6. [Medline].

  12. 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. 1998 Apr. 88(4):1071-5. [Medline].

  13. Weinberg G, Ripper R, Feinstein DL, Hoffman W. Lipid emulsion infusion rescues dogs from bupivacaine-induced cardiac toxicity. Reg Anesth Pain Med. 2003 May-Jun. 28(3):198-202. [Medline].

  14. 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. 2006 Jul. 105(1):217-8. [Medline].

  15. Litz RJ, Roessel T, Heller AR, Stehr SN. Reversal of central nervous system and cardiac toxicity after local anesthetic intoxication by lipid emulsion injection. Anesth Analg. 2008 May. 106(5):1575-7, table of contents. [Medline].

  16. 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. 2006 Aug. 61(8):800-1. [Medline].

  17. Foxall G, McCahon R, Lamb J, Hardman JG, Bedforth NM. Levobupivacaine-induced seizures and cardiovascular collapse treated with Intralipid. Anaesthesia. 2007 May. 62(5):516-8. [Medline].

  18. Zimmer C, Piepenbrink K, Riest G, Peters J. [Cardiotoxic and neurotoxic effects after accidental intravascular bupivacaine administration. Therapy with lidocaine propofol and lipid emulsion]. Anaesthesist. 2007 May. 56(5):449-53. [Medline].

  19. Ludot H, Tharin JY, Belouadah M, Mazoit JX, Malinovsky JM. Successful resuscitation after ropivacaine and lidocaine-induced ventricular arrhythmia following posterior lumbar plexus block in a child. Anesth Analg. 2008 May. 106(5):1572-4, table of contents. [Medline]. [Full Text].

  20. Warren JA, Thoma RB, Georgescu A, Shah SJ. Intravenous lipid infusion in the successful resuscitation of local anesthetic-induced cardiovascular collapse after supraclavicular brachial plexus block. Anesth Analg. 2008 May. 106(5):1578-80, table of contents. [Medline]. [Full Text].

  21. Marwick PC, Levin AI, Coetzee AR. Recurrence of cardiotoxicity after lipid rescue from bupivacaine-induced cardiac arrest. Anesth Analg. 2009 Apr. 108(4):1344-6. [Medline]. [Full Text].

  22. Weinberg GL, Di Gregorio G, Ripper R, et al. Resuscitation with lipid versus epinephrine in a rat model of bupivacaine overdose. Anesthesiology. 2008 May. 108(5):907-13. [Medline].

  23. Di Gregorio G, Schwartz D, Ripper R, et al. Lipid emulsion is superior to vasopressin in a rodent model of resuscitation from toxin-induced cardiac arrest. Crit Care Med. 2009 Mar. 37(3):993-9. [Medline].

  24. Mayr VD, Mitterschiffthaler L, Neurauter A, et al. A comparison of the combination of epinephrine and vasopressin with lipid emulsion in a porcine model of asphyxial cardiac arrest after intravenous injection of bupivacaine. Anesth Analg. 2008 May. 106(5):1566-71, table of contents. [Medline].

  25. Harvey M, Cave G, Kazemi A. Intralipid infusion diminishes return of spontaneous circulation after hypoxic cardiac arrest in rabbits. Anesth Analg. 2009 Apr. 108(4):1163-8. [Medline].

  26. Hayes BD, Gosselin S, Calello DP, Nacca N, Rollins CJ, Abourbih D, et al. Systematic review of clinical adverse events reported after acute intravenous lipid emulsion administration. Clin Toxicol (Phila). 2016 Jun. 54 (5):365-404. [Medline].

  27. Weinberg G. LipidRescue: resuscitation for cardiac toxicity. Available at http://www.lipidrescue.org/.

  28. Hiller DB, Gregorio GD, Ripper R, Kelly K, Massad M, Edelman L, et al. Epinephrine impairs lipid resuscitation from bupivacaine overdose: a threshold effect. Anesthesiology. 2009 Sep. 111(3):498-505. [Medline].

 
Previous
Next
 
Table 1. Epinephrine Content Examples
Solution Volume 1:100,000 (1 mg/100 mL) 1:200,000 (1 mg/200 mL)
1 mL 0.01 mg 0.005 mg
5 mL 0.05 mg 0.025 mg
10 mL 0.1 mg 0.05 mg
20 mL 0.2 mg 0.1 mg
Example: 50 mL of 1% lidocaine with epinephrine 1:100,000 contains lidocaine 500 mg and epinephrine 0.5 mg.
Table 2. Local Anesthetic Agents Used Commonly for Infiltrative Injection
Agent Duration of Action Maximum Dosage Guidelines (Total Cumulative Infiltrative Injection Dose per Procedure*)
Esters
Procaine (Novocaine) Short (15-60 min) 7 mg/kg; not to exceed 350-600 mg
Chloroprocaine (Nesacaine) Short (15-30 min) Without epinephrine: 11 mg/kg; not to exceed 800 mg total dose



With epinephrine: 14 mg/kg; not to exceed 1000 mg



Amides
Lidocaine (Xylocaine) Medium (30-60 min) Without epinephrine: 4.5 mg/kg; not to exceed 300 mg
Lidocaine with epinephrine Long (120-360 min) With epinephrine: 7 mg/kg
Mepivacaine (Polocaine, Carbocaine) Medium (45-90 min) Long (120-360 min with epinephrine) 7 mg/kg; not to exceed 400 mg
Bupivacaine (Marcaine) Long (120-240 min) Without epinephrine: 2.5 mg/kg; not to exceed 175 mg total dose
Bupivacaine with epinephrine Long (180-420 min) With epinephrine: Not to exceed 225 mg total dose
Etidocaine (Duranest)



No longer available in United States



Long (120-180 min) Without epinephrine: 0.4 mg/kg; not to exceed 300 mg total dose



With epinephrine: 8 mg/kg



Prilocaine (Citanest) Medium (30-90 min) Body weight < 70 kg: 8 mg/kg; not to exceed 500 mg



Body weight >70 kg: 600 mg



Ropivacaine (Naropin) Long (120-360 min) 5 mg; not to exceed 200 mg for minor nerve block
*Nondental use, administer by small incremental doses; administer the smallest dose and concentration required to achieve desired effect; avoid rapid injection.
Table 3. Minimum Intravenous Toxic Dose of Local Anesthetic in Humans [2]
Agent Minimum Toxic Dose (mg/kg)
Procaine 19.2
Tetracaine 2.5
Chloroprocaine 22.8
Lidocaine 6.4
Mepivacaine 9.8
Bupivacaine 1.6
Etidocaine 3.4
Previous
Next
 
 
 
 
 
All material on this website is protected by copyright, Copyright © 1994-2016 by WebMD LLC. This website also contains material copyrighted by 3rd parties.