local anesthetics toxicity and management
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Local Anesthetics Toxicity and Management. Gregory Pate, MD Department of Anesthesia Bremerton Naval Hospital. Local Anesthetic Toxicity Topics. Local Anesthetic Pharmacology Adverse Reactions to Local Anesthetics Types of Toxicity Acute Systemic Toxicity - PowerPoint PPT PresentationTRANSCRIPT
Local Anesthetics Toxicity and Management
Gregory Pate, MDDepartment of Anesthesia Bremerton Naval Hospital
Local Anesthetic Toxicity Topics
Local Anesthetic PharmacologyAdverse Reactions to Local AnestheticsTypes of ToxicityAcute Systemic Toxicity Management of Acute Systemic Toxicity
Basics: Local Anesthetic Pharm
Amino esters and Amino amidesMetabolismProtein bindingLipophilic-hydrophilic balanceHydrogen Ion concentration
Katzung, Basic & clinical pharm, 10th edition
Basics: Local Anesthetic Mechanism Active form of the local anestheticModulated receptor theoryOther possible mechanisms of action
Miller’s Anesthesia, 6th edition
Local Anesthetic Toxicity Topics
Local Anesthetic PharmacologyAdverse Reactions to Local AnestheticsTypes of ToxicityAcute Systemic Toxicity Management of Acute Systemic Toxicity
Methemoglobinemia
Prilocaine and BenzocaineBenzocaine sprays like CetacaineEMLA cream which has prilocaine although this practice is still generally considered safe Seen with use of prilocaine in epidurals around at 500-600mg for adults Dapsone, antibiotics, nitrates, etc.
Methemoglobin related to local anesthetics, Guay et al, 2009
Methemoglobinemia
Hypersensitivity Reactions
IgE mediated vs Non-IgE mediatedPerioperative anaphylaxis about 1:10,000 cases-NMBD, antibiotics, latex Does not take much allergenTrue allergy to amides very rareTrue allergy to esters like cocaine, procaine, chloroprocaine more common
Anaphylaxis and Anesthesia, Dewachter, 2009
Features of Anaphylaxis Airway: stridor, hoarseness, laryngeal edema, dyspnea, cyanosis, bronchospasm, and obstructionCardiac: tachycardia, hypotension, arrhythmia, cardiac arrest Neuro: dizzy, weak, syncopal, seizure Skin: flushing, erythema, pruritis, angioedema, maculopapular rash
Diagnoss and Management of Anaphylaxis, CMAJ, 2003
Acute Anaphylaxis
Diagnoss and Management of Anaphylaxis, CMAJ, 2003
Biphasic Anaphylaxis
Diagnoss and Management of Anaphylaxis, CMAJ, 2003
Local Anesthetic Toxicity Topics
Local Anesthetic PharmacologyAdverse Reactions to Local AnesthesticsTypes of ToxicityAcute Systemic Toxicity Management of Acute Systemic Toxicity
Types of Local Anesthetic Toxicity
LOCALIZED TOXICITYNeurotoxicityMyotoxicity
SYSTEMIC TOXICITYCNS toxicityCVS toxicity
NeurotoxicityDose/concentrationDuration of nerve exposureMost common with continuous spinal anesthesiaAll amino amides/ amino esters can cause direct toxicity
American Journal of Therapeutics, Cont Spinal Anesthesia, Moore, 2009
MyotoxicityEdema and necrosis after exposure to LidocaineNormally limited and reversibleOften reported in Ophthalmology
Zink et al., 2005
Prevention of LA toxicity
Dosing is a key factor in preventionReview Therapeutic Index
Local Anesthetic Toxicity Topics
Local Anesthetic PharmacologyAdverse Reactions to Local AnestheticsTypes of ToxicityAcute Systemic Toxicity Management of Acute Systemic Toxicity
LA toxicity - CNS
Local Anesthetics readily cross the blood-brain barrierCNS toxicity is drug/dose dependentClinical indicators of CNS toxicity
Kreitzer, Journal of Clinical Anesthesia, 1996
Dose Dependent Systemic Effects
Effects of Lidocaine by plasma concentration
CONC(mcg/mL) EFFECT 1–5 Analgesia 5–10 Lightheaded, Tinnitus, Tongue numbness 10–15 Seizure, LOC 15–25 Coma, resp arrest >25 CV depression
Barash, 5th pp464
Relative Potency for Toxicity (CVS:CNS) Toxicity
▪AGENT ▪RELATIVE POTENCY FOR CNS
TOXICITY
▪CVS:CNS
Bupivacaine 4 2L-bupivacaine 2.9 2Etidocaine 2 4.4Lidocaine 1 7.1Mepivacaine 1.4 7.1Ropivacaine 2.9 2
Barash, 5th edition pp462
LA Toxicity - CVS
Newer amino amide local anesthetics potential to cause CNS toxicityIndicators of CVS toxicityMechanism of toxicity
Albright, Anesthesiology,1979Clarkson, Anesthesiology, 1985
Seizure 30% smaller
dose for Bup than othersDysrhythmia
(a) Bup 13.2 mg/kg
(b) L-Bup 43.7mg/kg
(c) Rop 91.8 mg/kg
Shigeo, Anesth Analg 2001
EKG in CVS Toxicity
Kim, Canadian J of Anesthesia, 2003
Local Anesthetic Toxicity Topics
Local Anesthetic PharmacologyAdverse Reactions to Local AnestheticsTypes of ToxicityAcute Systemic Toxicity Management of Acute Systemic Toxicity
Early Options to Treat LA Toxicity
Epinephrine and AtropineShock, Shock, ShockOther ACLS MilrinoneVersed PropofolCPB
Early Options to Treat LA Toxicity Figure 1. Lethal dose-response curves for bupivacaine in the presence or absence of verapamil and nimodipine. B =
bupivacaine, N + B = nimodipine 200 [micro sign]g/kg + bupivacaine, V + B = verapamil 150 [micro sign]g/kg + bupivacaine.
Adsan, Anesth Analg, 1998
A FRESH IDEA
Lipid Emulsions expand the list of optionsA Decade of research and a growing body of evidence and case reportsThe Rescue Kit
Weinberg, LipidRescue.com, 2008
First To Benefit from Lipid Emulsion
Promising experiments with LA toxicity and Lipid Emulsion resuscitation Success leads to expanded research
Weinberg, Anesthesiology, 1998
Lipid Sink Hypothesis
Lipid infusionLipid phaseHighly lipophilic amino amidesDecreased unbound fraction
Weinberg, Anesthesiology, 1998
Group Treatment MAP mmHg
HR PaO2 PaCO2 pH
Saline Baseline 91 +/-12
122 +/-17
236 +/-69
36 +/-2
7.38 +/-.04
Saline Recovery 10 +/-3
ASYS
Lipid Baseline 96 +/-14
128 +/-21
228 +/- 63
35 +/-2
7.39 +/-.02
Lipid Recovery 93 +/-12
126 +/- 18
212 +/-56
36 +/-2
7.35 +/- .04
Studies with Lipid Emulsions in a Dog Model
Weinberg et al, Lipid emulsion infusion rescues dogs, 2003
First Lipid Emulsion Resuscitation after Bupivacaine toxicity/arrest
20 min of advanced cardiac life support, a total of 3 mg epinephrine, given in divided doses, 2 mg atropine, 300 mg amiodarone, and 40 U arginine vasopressin were administered. In addition, monophasic defibrillation was used at escalating energy levels-200, 300, 360, and 360 J, according to the advanced cardiac life support protocol. Cardiac rhythms included ventricular tachycardia with a pulse, pulseless ventricular tachycardia that momentarily became ventricular fibrillation, and eventually asystole. The arrhythmias observed during most of the resuscitation period were pulseless ventricular tachycardia and asystole.
Rosenblatt, Anesthesiology, 2006
Further Case Studies on LE
LipidRescue lists several case reports of successful resuscitation with LE after CVS toxicity with life threatening rhythms or asystole.Inferior to randomized double-blinded trials but such investigations would clearly be unethicalNot many case studies giving an account of an unsuccessful resuscitation effort with or without LE although we know such events have occurred
Weinberg, Correspondence, 2008
Applications of Intralipid in ED
Intralipid has been used to treat other types of drug overdoseCase studies are on the Lipidrerscue.org website.Same lipid sink idea
The Big Question– Lipid Emulsions are
NO SUBSTITUTE for ACLS.
– Where do we insert lipid emulsion administration into the ACLS algorithm?
– How is the drug given?
Weinberg, correspondence, 2008
primum non nocere Risks of Lipid Emulsion Infusion: all < 1%
Modulation of cytokine production by WBCsAltered inflammatory responseWeakness, altered MS, seizures in childrenFat emboli if lipid particles >5 microns in diameterHyperlipedemiaPulmonary hypertension anaphylaxis especially if prepared from soybean oil (most likely adverse reaction with acute, short-term administration)
ReferencesArthur GR: Alterations in the pharmacokinetic properties of amide local anesthetics following local anesthetic induced convulsions. Acta Anaesthesiol Scand 32:522, 1988Barash P: Clinical Anesthesia, 5th edition, chapter 17, 2006 Clarkson C: Mechanism for bupivacaine depression of cardiac conduction: fast block of sodium channelsduring the action potential with slow recovery from block during diastole. Anesthesiology 1985;62:396-405.Colin J: Intravenous ropivacaine bolus is a reliable marker of intravascular injection in premedicated healthyVolunteers. Canadian Journal of Anesthesia50: 8 / pp 795–800, 2003Cotileas P: Bupivacaine-Induced Myocardial Depression and Pulmonary Edema: A Case Report. Journal of Electrocardiology Vol. 33 No. 3 2000 Katzung B: Basic & Clinical Pharmacology, 10th Edition, Chapter 26 Kim J: Continuous mixed venous oxygen saturation, not mean blood pressure, is associated with early bupivacaine cardiotoxicity in dogs. Canadian Journal of Anesthesia 50:376-381 (2003)Mather L: Acute Toxicity of LA: Underlying Pharmacokinetic and Pharmacodynamic Concepts, Regional Anesthesia and Pain Medicine, Vol 30, No. 6, 2005 Miller R: Miller’s Anesthesia, 6th Edition, Chapter 14, 2005Mischa J: The effects of Age on Neural Blockade and Hemodynamic Changes After Epidural Anesthesia with Ropivacaine. International Anesthesia Research Society, 94(5): 1325-1330, 2002Morgan and Mikhail, 4th edition, Chapter 14, 2006 Rosenberg H: maximum Recommended Doses of Local Anesthetics: A multifactorial Concept. American Society of Regional Anesthesia and Pain Medicine, 29 (6):564-575, 2004ScottD: EDITORIAL: “Maximum Recommended Doses” of Local Anesthetic Drugs. British Journal of Anesthesia Vol 63, No. 4, 1989.Shigeo O: Systemic Toxicity and Resuscitation in Bupivacaine, Levobupivacaine, or Ropivacaine Infused Rats. Anesth Analg 2001;93:743–8)Weinberg G: Lipid emulsion infusion rescues dogs from Bupivacaine induced cardiac toxicity. Regional Anesthesia and Pain Medicine, Vol 28, No 3 :198-202, 2003 Weinberg G: Pretreatment or Resuscitation with a Lipid Infusion Shifts the Dose-Response to Bupivacaine-induced Asystole in Rats. Anesthesiology:Volume 88(4)April 1998pp 1071-1075 Warren J: Reversal of Central Nervous System and Cardiac Toxicity After Local Anesthetic Intoxication by Lipid Emulsion Injection. International Anesthesia Research Society, Volume 106(5):1578-1580, 2008 Yokoyama M: Effect of Vasoconstrictive Agents added to lidocaine on IV lidocaine-induced convulsions in rats. Anesthesiology 82:574,1995