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Toxicity of Local Anesthetics A. Borgeat Balgrist University Hospital, Zurich Switzerland Faculty Disclosure X No, nothing to disclose Yes, please specify: Company Name Honoraria/ Expenses Example: Company XYZ x Consulting/ Advisory Board Funded Research x Royalties/ Patent Stock Options Equity Position Ownership/ Employee Other (please specify) x Off-Label Product Use Will you be presenting or referencing off-label or investigational use of a therapeutic product? X No Yes, please specify: The fate of local anesthetics Artery Vein 97- 98% LA +/- 30% Nerve 2-3% Systemic resorption depends on local blood flow! Heavner JE. Curr Opin Anaesthesiol 2007; 20:336-42. Review Cox B et al. Best Pract Res Clin Anaesthesiol 2003; 17:111-36 Systemic Complications Acute CNS toxicity Cardiotoxicity CNS Toxicity The key issue: Understanding the physiopathology Stage of CNS-Depression Coma, Apnea, Depression, Hypotension Convulsive Stage General, tonic-clonic Seizures Preconvulsive Stage Tremor, Tinnitus, Nystagmus, clouding of consciousness First Stage numbness, metalic flavour, dysgeusea tachycardia LA-Concentration Systemic Toxicity - Clinical Symptoms Regional anesthesia and seizures (retrospective study) Block number Caudal (adults) Axillary Interscalene Supraclavicular Epidural 1295 6620 659 253 16870 seizures n (%) 9 (0.7) 8 (0.1) 5 (0.7) 2 (0.8) 2 (0.01) Total incidence 0.1% (1/1000 blocks) Brown et al. Anesth Analg 1995;81:321, Seizures after PNB (prospective study) Interscalene block Supraclavicular block Axillary block Mid-humeral block Psoas compartment block Femoral block Sciatic block Popliteal block Performed Seizure 3‘459 1‘899 11‘024 7‘402 394 10‘309 8‘507 952 0 1 1 1 1 0 2 0 Auroy et al. Anesthesiology 2002;97:1274, Factors influencing CNS toxicity • the concentration • the speed of increase „The higher the plasma level and the faster it increases, the more likely an adverse systemic response is about to happen“. • patient status (heart, liver, nutritional) CNS Toxicity LA concentration (brain epilepsy) threshold time Effect of pH and pCO2 on Toxicity Alexander et al. Can J Anaesth 1987; 34:343, Rendoing et al. Anesth Analg 1969;26,445, Interaction Propofol - Remifentanil I.V. ropi vs bupi 10 mg/min in volunteers: Mean threshold plasma concentration for CNS toxicity Arterial Plasma conc (mg/L) Total Free Ropivacaine 4.3 (3.4-5.3) 0.55 (0.34-0.84) Bupivacaine 4.0 (1.1-6.2) 0.30 (0.13-0.51) Knudsen et al. Br J Anaesth 1997;78:507 Is a recommended maximum LA dose reliable ? • No • Site of injection • Uncontrolled factors (quick reabsorption) • Individual variations in PK/PD and tolerability instead: recommended effective dose, be prepared for toxic reactions Factors influencing toxicity physico-chemical properties local perfusion vasoconstrictor adjuvants chemical structure intrinsic vasoactivity cardio-vascular disease liver disease systemic absorption renal dysfunction „toxic“ dose of local anesthetics injection site protein binding pregnancy age height and weight individual pharmacodynamics volume of distribution metabolism/excretion acidosis/temperature drug interaction Can we avoid intravascular injection of LA ? • IV injection is rare, except for deep block • Slow administration • Repeated aspiration (cave deep block) • Close verbal control with patient • Watch out for progressive increase in heart rate (with or without adrenaline) CNS toxicity of LA • Initial symptoms from organs with large cortical representation • Convulsion may be the first symptom after IV (accidental) injection – especially with bupivacaine - Toxicity: when does it occur ? Plasma concentration of total ropivacaine Group 18mg/h Group 12mg/h mg/l mg/l Toxicity: when does it occur ? Free fraction of ropivacaine Group 12mg/h % Group 18mg/h % Toxicity: when does it occur ? Plasma concentration of -1-glycoprotein Group 12mg/h mol/L Group 18mg/h mol/L Booker et al Br J Anaesth 1996;76:365, male female Effect of age on the serum concentration of AAG in 35 male and 33 female subjects Veering et al. Br J Clin Pharmac 1990;29:201, CNS toxicity: Physiopathology Normal CNS activity LA concentration G A B A CNS toxicity: treatment • Stop administration (if not too late!) • Oxygen 100% • Avoid acidosis Therapy of systemic Toxicity CNS depression respiratory depression Acidosis pH; pCO2 cerebral blood flow LA-H+ „ion trapping“ accumulation of LA in the CNS Plasma protein-binding free [LA] in plasma Alexander et al. Can J Anaesth 1987; 34:343, Rendoing et al. Anesth Analg 1969;26,445, CNS toxicity: treatment • Stop administration (if not too late!) • Oxygen 100% • Avoid acidosis • Anticonvulsant CNS toxicity: treatment • midazolam • propofol CNS hyperexcitability successfully blocked by both drugs 3.5 min 13.5 min CNS Toxicity • Systemic neurotoxicity can always occur even in the best hands • Treatment is usually easy and successful • Propofol possesses the best PK/PD profile to treat (avoid) convulsion Systemic toxicity of LA: why the brain first ? CNS one system against another cardiac one or more receptors blocked Cardiac Toxicity The key issue: Understanding the physiopathology Cardiotoxicity The most serious issue when dealing with local anesthetics Systemic Toxicity - Clinical Symptoms Stage of CNS-Depression Coma, Apnea, Depression, Hypotension Convulsive Stage General, tonic-clonic Seizures Preconvulsive Stage Tremor, Tinnitus, Nystagmus, clouding of consciousness First Stage numbness, metalic flavour, dysgeusea tachycardia LA-Concentration direct cardiac depression cardiac arrest hypotension ischemia AV-dissociation arrhythmia, bradycardia ECG-widening low output indirect cardiac depression hypertension, tachycardia, arrhythmia Cardiotoxicity of local anesthetics ADP ATP Sodium Channel Mitochondria Calcium Channel Potassium Channel Local anesthetics : physiochemical properties Lidocaine Mepivacaine Bupivacaine Levobupivacaine Ropivacaine pKa Lipid solubility Protein binding 7.8 7.7 2.9 0.8 64 % 77 % 8.1 27 95 % 8.1 14 94 % Cardiotoxicity of LA : effect on sodium channel Affinity for Na+ channels Lidoc Ropiv Bupiv Fast in Fast out Fast in Intermediate out Fast in Slow out 1.4 1.9 10 5 Time constant for recovery from Na+ 0.19 channel block (sec) Arrhythmia threshold (mmol/kg) 20 Reiz et al. Acta Anaesth Scand 1989;33:93, Cardiotoxicity of LA : effects on ATP % Inhibition 100 * 40 0 Bupi 3mM P < 0.05 Ropi 3mM Sztark et al. Anesthesiology 1998;88:1340, cumulative doses (mg/kg) Systemic Toxicity (Rat Model) Bupivacaine Levobupivacaine Ropivacaine ~1:2 * p<0.05 vs. Bupivacaine + p<0.05 vs. Levobupivacaine seizure arrhythmia asystolia Ohmura S, et al.; Anesth Analg 2001; 93:743-8 Systemic Toxicity (Rat Model) Bupivacaine n=11 Levobupivacaine n=10 Ropivacaine* n=11 Ohmura S, et al.; Anesth Analg 2001; 93:743-8 Cardiotoxicity of LA : outcome after cardiovascular collapse % Bupivacaine Levo-Bupivacaine 50 Ropivacaine Lidocaine 30 10 1 Groban et al. Anesth Analg 2001;92:37 Cardiotoxicity of local anesthetics g/ml 6.8 (C) g/ml 4.0 1.6 2.2 6.3 4.2 3.1 L R LB 3.2 B g/ml 5.8 L 5.0 3.3 L R LB R LB B 3.6 B Groban et al. Reg Anesth Pain M 2002;27:460, Cardiotoxicity: treatment ropivacaine: 7 cases successfully treated with low dose of epinephrine bupivacaine: mortality still around 5-10% levobupivacaine: ? Physiochemical properties of LA implicated in cardiotoxicity • lipid solubility • size of the lateral chain • stereoselectivity Influence of stereoselectivity on cardiac toxicity Mechanism Effect Remark Affinity for the Na+ channels YesDecreased affinity Arrhythmogenic potential Yes/No Other mechanisms than inhibition of conduction are also implicated Myocardial depression No Lipid solubility and size of the molecule are mainly implicated Mitochondrial energy metabolism No Lipid solubility is mainly implicated Calcium homeostasis No Lipid solubility is mainly implicated Cardiotoxicity: treatment • CV resuscitation • Epinephrine • Intralipid (bupivacaine) Lipids for Local Anesthetics Has the Silver Bullet been Identified? Anaesthesia 2006;61:800, RAPM 2008;33:178, Anaesthesia 2007;62:516, Dillane D et al. Can J Anesth 2010; 57:368-80 Recovery time after asystolia (sec) Lipid-Studies on the isolated Heart (n=5) (n=5) (n=5) (n=5) (n=5) (n=5) 90% recovery of heart rate 90% recovery of cardiac product Zausig Y, et al. Anesth Analg 2009;109:1323 Lipid-Studies on the isolated Heart no significant differences regarding starting points • prophylactic substitution of lipids: significant duration till cardiac arrest for bupivacaine no significant differences for ropivacaine and mepivacaine Duration till cardiac arrest [sec] • Lipidrescu® = lipid-sinks time till cardiac arrest in sec * p <0,05. Zausig Y et. al. German Anaesthesia Meeting 2010 Protocol: Isolated rat hearts were perfused with or without intralipid before administration of bupivacaine or mepivacaine *p<0.05 Aumeier et al Br J Anaesth 2013;112:735, Protocol: Newborn piglets received levobupivacaine until CV collapse - Saline - Intralipid alone - Epinephrine alone - Intralipid + epinephrine De Queiroz et al Br J Anaesth 2014;112:729, Protocol: Infusion of bupivacaine till drop of blood pressure >50% of the initial value epinephrine 3 ug/kg intralipid 20% 2 ml/kg intralipid 20% 4 ml/kg Mauch J et al. Paed Anaesth 2011; 21:1103, Notably, ILE has been used effectively in treating overdose of many common prescription medications (e.g. beta blockers, tricyclic antidepressants or calcium channel blockers) that can be highly resistant to standard resuscitation measures. Identifying the precise mechanism(s) underlying ILE holds the promise of improving its efficacy and providing an effective, generic antidotal treatment for a range of life-threatening toxic drug overdoses. However, the precise mechanisms of ILE are not well understood. The conventional explanation involves partitioning of the offending toxin into the newly created lipemic plasma phase, or 'lipid sink'. However, even this mechanism has not been tested rigorously in vivo. Moreover, we have observed that key aspects of ILE cannot be explained by the sink alone, indicating that other, less well-understood, mechanisms are also at play. We believe that ILE also directly benefits cardiovascular function and have confirmed in preliminary experiments that the infusion of lipid emulsion in the intact rat exerts positive effecs on cardiac contractility and aortic blood flow. We hypothesize that this results in part from direc, positive effects of fatty acid metabolism on cardiac function. Moreover, it is wellestablished tha tissue ischemia can cause intercellular endothelial gaps to expand, thereby allowing liposomes to migrate into the myocardial interstitium. Such passive targeting of lipid particles, essentially nano-medicine, will bypass the normal tissue barriers to diffusion of drug away from cells and diminish the response time to lipid signal effectors. We hypothesize that extravascular migration of lipid particles contributes to the overall efficacy of ILE in reversing cardiac drug toxicity. W propose studies to test the metabolic effects of ILE and transendothelial migration of lipid particles. Finally, we seek to improve the translation of ILE to cocaine-related toxicity and longer-lasting overdoses such as calcium channel blocker toxicity. Improved patient safety and outcomes from drug toxicity are the over-arching goals of this project. However, the precise mechanisms of ILE are not well understood Weinberg et al National Inst of Health, 2015, abstract Adverse Reactions of intralipid 1. Those more frequently encountered are due either to a) contamination of the intravenous catheter and result in sepsis, or to b) vein irritation by concurrently infused hypertonic solutions and may result in thrombophlebitis. These adverse reactions are inseparable from the hyperalimentation procedure with or without Intralipid®. 2. Less frequent reactions more directly related to Intralipid® are: a) immediate or early adverse reactions, each of which has been reported to occur in clinical trials, in an incidence of less than 1%: dyspnea, cyanosis, allergic reactions, hyperlipemia, hypercoagulability, nausea, vomiting, headache, flushing, increase in temperature, sweating, sleepiness, pain in the chest and back, slight pressure over the eyes, dizziness, and irritation at the site of infusion, and, rarely, thrombocytopenia in neonates; b) delayed adverse reactions such as hepatomegaly, jaundice due to central lobular cholestasis, splenomegaly, thrombocytopenia, leukopenia, transient increases in liver function tests, and overloading syndrome (focal seizures, fever, leukocytosis, hepatomegaly, splenomegaly and shock). The deposition of a brown pigmentation in the reticuloendothelial system, the so-called “intravenous fat pigment,” has been reported in patients infused with Intralipid®. The causes and significance of this phenomenon are unknown. Retrospective chart review in two academic medical centers in the USA between 2005 and 2012 A total of nine patients were treated Levine et al J Med Toxicol 2014;10:10, Lipid-Infusion The Association of Anaesthetists of Great Britain & Ireland 2010 the Silver Bullet only for lipophilic drugs! Conclusions „Poison in the hand of an expert is medicine, medicine in the hand of a fool is poison Giacomo Girolamo Casanova (1725-1798),