Local anaesthetic systemic toxicity

Access the CPD MCQs for this issue online here ### Key points Well-placed local anaesthetics (LAs) can yield great clinical benefits. But systemic toxicity related to their use can be devastating. The highly publicized case in 2004 of Mayra Cabrera, a theatre nurse who died shortly after delivery of her baby boy when her epidural infusion of bupivacaine was mistakenly connected to her i.v. line, reminds us to be vigilant and to learn from such rare events. While prevention is clearly the most important element in avoiding morbidity and mortality associated with local anaesthetic systemic toxicity (LAST), such cases still occur despite best practice. Knowing how to manage these uncommon events is vital. In this review, we cover LA toxicity, its incidence, clinical features, risk factors, prevention, and management and examine i.v. lipid emulsion (ILE) therapy in more detail. LAST has been recognized for more than a hundred years, but the precise incidence is currently unknown. In 1928, the American Medical Association reported 40 deaths attributable to LAs.1 Cocaine was responsible for half of these deaths, but procaine was also implicated. These findings prompted the search for less toxic agents. Lidocaine, first synthesized in 1944, was the first amide LA to be used clinically. However, in 1979, the potentially fatal toxicity of amide LAs was highlighted by Albright.2 More recently, studies from 1993 …

[1]  T. Short,et al.  Management of severe local anaesthetic toxicity , 2010 .

[2]  A. Hutton Oxford Handbook of Anaesthesia, 2nd edn , 2006 .

[3]  N. Woodall,et al.  Combined nebulization and spray-as-you-go topical local anaesthesia of the airway. , 2005, British journal of anaesthesia.

[4]  S. Gosselin,et al.  Analytical interferences resulting from intravenous lipid emulsion , 2012, Clinical toxicology.

[5]  M. Morais‐Almeida,et al.  Allergy to local anesthetics of the amide group with tolerance to procaine , 2003, Allergy.

[6]  B. Covino,et al.  Treatment of acute systemic toxicity after the rapid intravenous injection of ropivacaine and bupivacaine in the conscious dog. , 1991, Anesthesia and analgesia.

[7]  A. Bader,et al.  Measurements of protein binding of lidocaine throughout pregnancy. , 1994, Anesthesia and analgesia.

[8]  P. Frascarolo,et al.  A Comparison of the Electrocardiographic Cardiotoxic Effects of Racemic Bupivacaine, Levobupivacaine, and Ropivacaine in Anesthetized Swine , 2000, Anesthesia and analgesia.

[9]  J. Eisenkraft,et al.  Successful use of a 20% lipid emulsion to resuscitate a patient after a presumed bupivacaine-related cardiac arrest. , 2006, Anesthesiology.

[10]  D. Schroeder,et al.  Regional Anesthesia and Local Anesthetic-Induced Systemic Toxicity: Seizure Frequency and Accompanying Cardiovascular Changes , 1995, Anesthesia and analgesia.

[11]  H. Nelson,et al.  An approach to the patient with a history of local anesthetic hypersensitivity: experience with 90 patients. , 1979, The Journal of allergy and clinical immunology.

[12]  G. Strichartz,et al.  Fundamental Properties of Local Anesthetics. II. Measured Octanol: Buffer Partition Coefficients and pKa Values of Clinically Used Drugs , 1990, Anesthesia and analgesia.

[13]  S. Ohmura,et al.  Systemic Toxicity and Resuscitation in Bupivacaine-, Levobupivacaine-, or Ropivacaine-Infused Rats , 2001, Anesthesia and analgesia.

[14]  M. Behbehani,et al.  Cardiovascular Toxicity of Local Anesthetics: An Alternative Hypothesis , 1986, Anesthesia and analgesia.

[15]  J. Butterworth,et al.  Cardiac Resuscitation After Incremental Overdosage with Lidocaine, Bupivacaine, Levobupivacaine, and Ropivacaine in Anesthetized Dogs , 2001, Anesthesia and analgesia.

[16]  T. Meek,et al.  Lipid emulsion to treat overdose of local anaesthetic: the gift of the glob , 2006, Anaesthesia.

[17]  M. Mulroy Systemic Toxicity and Cardiotoxicity From Local Anesthetics: Incidence and Preventive Measures , 2002, Regional Anesthesia & Pain Medicine.

[18]  B. Veering Complications and local anaesthetic toxicity in regional anaesthesia , 2003, Current opinion in anaesthesiology.

[19]  G. Weinberg,et al.  Pretreatment or Resuscitation with a Lipid Infusion Shifts the Dose‐Response to Bupivacaine‐induced Asystole in Rats , 1998, Anesthesiology.

[20]  J. Tamargo,et al.  Stereoselective block of a human cardiac potassium channel (Kv1.5) by bupivacaine enantiomers. , 1995, Biophysical journal.

[21]  S. Grevsten,et al.  The Influence of Acid‐Base Changes on Central Nervous System Toxicity of Local Anaesthetic Agents II , 1974, Acta anaesthesiologica Scandinavica.

[22]  G A Albright,et al.  Cardiac arrest following regional anesthesia with etidocaine or bupivacaine. , 1979, Anesthesiology.

[23]  J. Butterworth,et al.  Does Local Anesthetic Stereoselectivity or Structure Predict Myocardial Depression in Anesthetized Canines? , 2002, Regional Anesthesia & Pain Medicine.

[24]  Lorri A. Lee,et al.  Injuries Associated with Regional Anesthesia in the 1980s and 1990s: A Closed Claims Analysis , 2004, Anesthesiology.

[25]  K. Jamrozik,et al.  Preliminary Results of the Australasian Regional Anaesthesia Collaboration: A Prospective Audit of More Than 7000 Peripheral Nerve and Plexus Blocks for Neurologic and Other Complications , 2009, Regional Anesthesia & Pain Medicine.

[26]  K.,et al.  Central nervous and cardiovascular effects of i.v. infusions of ropivacaine, bupivacaine and placebo in volunteers. , 1997, British journal of anaesthesia.

[27]  P. Hopkins Ultrasound guidance as a gold standard in regional anaesthesia. , 2007, British journal of anaesthesia.

[28]  G. Weinberg Lipid Emulsion Infusion: Resuscitation for Local Anesthetic and Other Drug Overdose , 2012, Anesthesiology.

[29]  S. Stehr,et al.  Successful resuscitation of a patient with ropivacaine‐induced asystole after axillary plexus block using lipid infusion * , 2006, Anaesthesia.

[30]  L. Mather Disposition of mepivacaine and bupivacaine enantiomers in sheep. , 1991, British journal of anaesthesia.

[31]  P. Wouters,et al.  Long-chain triglycerides improve recovery from myocardial stunning in conscious dogs. , 1996, Cardiovascular research.

[32]  M. Lakhal,et al.  Electrophysiological study in the dog of the risk of cardiac toxicity of bupivacaine. , 1987, Archives internationales de pharmacodynamie et de therapie.

[33]  J. Butterworth,et al.  Molecular Mechanisms of Local Anesthesia: A Review , 1990, Anesthesiology.

[34]  Bruno Falissard,et al.  Major Complications of Regional Anesthesia in France: The SOS Regional Anesthesia Hotline Service , 2002, Anesthesiology.

[35]  T. Mashimo,et al.  The α and γ subunit-dependent effects of local anesthetics on recombinant GABAA receptors , 2000 .

[36]  M. Behbehani,et al.  Enantiomer-Specific Effects of an Intravenously Administered Arrhythmogenic Dose of Bupivacaine on Neurons of the Nucleus Tractus Solitarius and the Cardiovascular System in the Anesthetized Rat , 1992, Regional Anesthesia & Pain Medicine.

[37]  C. Valdivia,et al.  Fatty acids antagonize bupivacaine - induced INa blockade , 2011, Clinical toxicology.

[38]  S. Deutsch,et al.  Cardiac arrest after interscalene brachial-plexus block. , 1977, Anesthesia and analgesia.

[39]  J. Heavner Cardiac Dysrhythmias Induced by Infusion of Local Anesthetics into the Lateral Cerebral Ventricle of Cats , 1986, Anesthesia and analgesia.

[40]  K. Dhunér,et al.  Studies on the duration of local anaesthesia: structure/activity relationships in a series of homologous local anaesthetics. , 2009, Acta pharmacologica et toxicologica.

[41]  M. Sasada,et al.  Drugs in Anaesthesia and Intensive Care , 1990 .

[42]  M. Rosen,et al.  Bupivacaine-induced cardiac arrhythmias in sheep. , 1984 .

[43]  S. Y. Wang,et al.  Residues in Na(+) channel D3-S6 segment modulate both batrachotoxin and local anesthetic affinities. , 2000, Biophysical journal.

[44]  D. Scott,et al.  Factors affecting plasma levels of lignocaine and prilocaine. , 1972, British journal of anaesthesia.

[45]  P. Rosenberg,et al.  Maximum Recommended Doses of Local Anesthetics: A Multifactorial Concept , 2004, Regional Anesthesia & Pain Medicine.

[46]  R. Prielipp,et al.  Bupivacaine Inhibits Cyclic‐3', 5'‐Adenosine Monophosphate Production A Possible Contributing Factor to Cardiovascular Toxicity , 1993, Anesthesiology.

[47]  K. Samii,et al.  Myocardial uptake of bupivacaine: II. Pharmacokinetics and pharmacodynamics of bupivacaine enantiomers in the isolated perfused rabbit heart. , 1993, Anesthesia and analgesia.

[48]  G. Weinberg,et al.  Rapid Cardiotonic Effects of Lipid Emulsion Infusion* , 2013, Critical care medicine.

[49]  B. Covino,et al.  Acute Cardiovascular Toxicity of Intravenous Amide Local Anesthetics in Anesthetized Ventilated Dogs , 1982, Anesthesia and analgesia.

[50]  Jm Dippenaar,et al.  Local anaesthetic toxicity , 2007 .

[51]  B. Akerman,et al.  Primary evaluation of the local anaesthetic properties of the amino amide agent ropivacaine (LEA 103) , 1988, Acta anaesthesiologica Scandinavica.

[52]  J. Butterworth Models and Mechanisms of Local Anesthetic Cardiac Toxicity: A Review , 2009, Regional Anesthesia & Pain Medicine.

[53]  D. M. Chernoff,et al.  Kinetic analysis of phasic inhibition of neuronal sodium currents by lidocaine and bupivacaine. , 1990, Biophysical journal.

[54]  J. Kantelip,et al.  Myocardial uptake of bupivacaine: I. Pharmacokinetics and pharmacodynamics of lidocaine and bupivacaine in the isolated perfused rabbit heart. , 1993, Anesthesia and Analgesia.

[55]  F. Reynolds Does the left hand know what the right hand is doing? An appraisal of single enantiomer local anaesthetics. , 1997, International journal of obstetric anesthesia.

[56]  K. Allman,et al.  Oxford handbook of anaesthesia , 2006 .

[57]  V. Adam,et al.  Local anaesthetic toxicity , 2011 .

[58]  D. Feinstein,et al.  Lipid Emulsion Infusion Rescues Dogs From Bupivacaine-Induced Cardiac Toxicity , 2003, Regional Anesthesia & Pain Medicine.

[59]  D. Stanski,et al.  CURARE NEUROMUSCULAR BLOCKADE DURING HYPOTHERMIA IN MAN , 1979 .

[60]  M. Barrington,et al.  Ultrasound Guidance Reduces the Risk of Local Anesthetic Systemic Toxicity Following Peripheral Nerve Blockade , 2013, Regional Anesthesia & Pain Medicine.

[61]  J. Butterworth,et al.  Structure-Affinity Relationships and Stereospecificity of Several Homologous Series of Local Anesthetics for the beta2-Adrenergic Receptor , 1997, Anesthesia and analgesia.

[62]  R. H. de Jong,et al.  Cardiovascular Effectsv of Convulsant and Supraconvulsant Doses of Amide Local Anesthetics , 1982, Anesthesia and analgesia.

[63]  M. Barile,et al.  Disparate role of Na(+) channel D2-S6 residues in batrachotoxin and local anesthetic action. , 2001, Molecular pharmacology.

[64]  R. Kaufmann,et al.  Adverse reactions to local anesthetics: analysis of 197 cases. , 1996, The Journal of allergy and clinical immunology.

[65]  F. Çeti̇nkaya Sensitivity to local anaesthetics among asthmatic children. , 2001, International journal of paediatric dentistry.

[66]  P. Lavand'homme,et al.  The Comparative Toxicity of Ropivacaine and Bupivacaine at Equipotent Doses in Rats , 2000, Anesthesia and analgesia.

[67]  P. Neuvonen,et al.  Effect of intravenous lipid emulsion on bupivacaine plasma concentration in humans , 2012, Anaesthesia.

[68]  Alistair Lee,et al.  Acute Toxicity of Ropivacaine Compared with That of Bupivacaine , 1989, Anesthesia and analgesia.

[69]  B. Veering,et al.  Cardiovascular and Central Nervous System Effects of Intravenous Levobupivacaine and Bupivacaine in Sheep , 1998, Anesthesia and analgesia.

[70]  M. Eghbali,et al.  Fatty-acid oxidation and calcium homeostasis are involved in the rescue of bupivacaine-induced cardiotoxicity by lipid emulsion in rats* , 2012, Critical care medicine.

[71]  Bupivacaine suppresses [Ca2+]i oscillations in neonatal rat cardiomyocytes with increased extracellular K+ and is reversed with increased extracellular Mg2+ , 2000 .

[72]  Kinetic effects of quaternary lidocaine block of cardiac sodium channels: a gating current study , 1994, The Journal of general physiology.

[73]  W. Harrop-Griffiths,et al.  Guidelines and the adoption of ‘lipid rescue’ therapy for local anaesthetic toxicity , 2009, Anaesthesia.

[74]  B. Covino,et al.  The Cardiovascular Effects of Convulsant Doses of Lidocaine and Bupivacaine in the Conscious Dog , 1985, Regional Anesthesia & Pain Medicine.

[75]  G. Edelman,et al.  Epinephrine Impairs Lipid Resuscitation from Bupivacaine Overdose: A Threshold Effect , 2009, Anesthesiology.

[76]  B. Covino,et al.  Comparative Systemic Toxicity of Convulsant and Supraconvulsant Doses of Intravenous Ropivacaine, Bupivacaine, and Lidocaine in the Conscious Dog , 1989, Anesthesia and analgesia.

[77]  B. Covino,et al.  Effect of Local Anesthetic Agents on Cardiac Conduction and Contractility , 1981, Regional Anesthesia & Pain Medicine.

[78]  G. Weinberg,et al.  Local anesthetic systemic toxicity: prevention and treatment. , 2011, Anesthesiology clinics.

[79]  L. Mather,et al.  Tolerability of large-dose intravenous levobupivacaine in sheep. , 2000 .

[80]  G. Johansson,et al.  Differential depressant and electrophysiologic cardiotoxicity of local anesthetics: an experimental study with special reference to lidocaine and bupivacaine. , 1986 .

[81]  J. Butterworth,et al.  Ventricular Arrhythmias With or Without Programmed Electrical Stimulation After Incremental Overdosage with Lidocaine, Bupivacaine, Levobupivacaine, and Ropivacaine , 2000, Anesthesia and analgesia.

[82]  G. Åberg Toxicological and local anaesthetic effects of optically active isomers of two local anaesthetic compounds. , 1972, Acta pharmacologica et toxicologica.

[83]  G. Weinberg Lipid infusion therapy: translation to clinical practice. , 2008, Anesthesia and analgesia.

[84]  J. Butterworth,et al.  Lipid Reversal of Bupivacaine Toxicity: Has the Silver Bullet Been Identified? , 2003, Regional Anesthesia & Pain Medicine.

[85]  L. Groban,et al.  Differences in cardiac toxicity among ropivacaine, levobupivacaine, bupivacaine, and lidocaine * , 2001 .

[86]  R. Partch,et al.  Scavenging Nanoparticles: An Emerging Treatment for Local Anesthetic Toxicity , 2005, Regional Anesthesia & Pain Medicine.

[87]  D. Galili,et al.  Evaluation of adverse reactions to local anesthetics: experience with 236 patients. , 2003, Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology.

[88]  S. Reiz,et al.  Cardiotoxicity of local anaesthetic agents. , 1986, British journal of anaesthesia.

[89]  N. Kellett,et al.  The Central Nervous System and Cardiovascular Effects of Levobupivacaine and Ropivacaine in Healthy Volunteers , 2003, Anesthesia and analgesia.

[90]  W. Dick Guidelines 2000 for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care , 2000, Notfall & Rettungsmedizin.

[91]  R. Sassi,et al.  Allergy to local anaesthetics in dentistry. Myth or reality? , 2002, Allergologia et immunopathologia.

[92]  J. Plummer,et al.  Direct cardiac effects of intracoronary bupivacaine, levobupivacaine and ropivacaine in the sheep , 2001, British journal of pharmacology.

[93]  Spencer S. Liu,et al.  Safety Steps for Epidural Injection of Local Anesthetics: Review of the Literature and Recommendations , 1997, Anesthesia and analgesia.

[94]  J. Apfelbaum,et al.  Local anesthetic systemic toxicity. , 2014, Aesthetic surgery journal.

[95]  Lawrence Litt,et al.  Serious Complications Related to Regional Anesthesia: Results of a Prospective Survey in France , 1997, Anesthesiology.

[96]  W. Runciman,et al.  Hemodynamic and Central Nervous System Effects of Intravenous Bolus Doses of Lidocaine, Bupivacaine, and Ropivacaine in Sheep , 1989, Anesthesia and analgesia.

[97]  H. Refsum,et al.  Cardiac electrophysiologic and hemodynamic effects related to plasma levels of bupivacaine in the dog. , 1985, Anesthesia and analgesia.

[98]  T. Meek,et al.  Antidotes to anesthetic catastrophe: lipid emulsion and dantrolene. , 2007, Anesthesia and analgesia.

[99]  S. Ahmed,et al.  Levobupivacaine or ropivacaine: A randomised double blind controlled trial using equipotent doses in spinal anaesthesia☆,☆☆ , 2016 .

[100]  L. Groban Central Nervous System and Cardiac Effects From Long-Acting Amide Local Anesthetic Toxicity in the Intact Animal Model , 2002, Regional Anesthesia & Pain Medicine.