Local anesthetic systemic toxicity

1. Local anestheticsystemic toxicity John Butterworth, MD Professor & Head Section on Cardiothoracic Anesthesiology Wake Forest University School of Medicine Winston-Salem, North Carolina

2. Local anestheticsystemic toxicity History Mechanisms Patterns of LA toxicity Summary

3. Early reports of LA mortality AMA committee reviews 57 deaths from LAs [Mayer et al JAMA 1924;82:876-85; JAMA 1928;90:1290-1] 3 deaths after 22,351 gastroscopies attributed to cocaine or tetracaine [Schindler Am J Dig Dis 1940;7:293] 7 deaths in 39,278 uses of cocaine or tetracaine in North American otolaryngology clinics [Ireland et al Laryngoscope 1951;61:767-77]

4. FDA and systemic toxicity from LAs Cardiac arrest without prior CNS toxicity bupivacaine & etidocaine (Albright, 1979) �Black box� warning in package insert Bupivacaine 1983 No �black box� warning Ropivacaine 1997 Levobupivacaine 1999)

5. Local anestheticsystemic toxicity History Mechanisms Patterns of LA toxicity Summary

6. LAs bind and inhibit many differing receptors and channels Channels Na Control

7. LAs bind and inhibit many differing receptors and channels Channels Na Ca (multiple types) K

8. LAs bind and inhibit many differing receptors and channels Channels Na Ca (multiple types) K

9. LAs bind and inhibit many differing receptors and channels Channels Na Ca K Enzymes Adenylyl cyclase

10. LAs bind and inhibit many differing receptors and channels Channels Na Ca (multiple types) K Enzymes Adenylyl cyclase Guanylyl cyclase Lipases

11. LAs bind and inhibit many differing receptors and channels Channels Na Ca (multiple types) K Enzymes Adenylyl cyclase Guanylyl cyclase Lipases Receptors Nicotinic acetylcholine NMDA �2-adrenergic

12. LAs bind and inhibit many differing receptors and channels Channels Na Ca (multiple types) K Enzymes Adenylyl cyclase Guanylyl cyclase Lipases Receptors Nicotinic acetylcholine NMDA �2-adrenergic Important for spinal, epidural, or systemic effects?

13. LAs bind and inhibit many differing receptors and channels Do not assume LA toxic side effects arise from Na channel inhibition!

14. Local anestheticsystemic toxicity History Mechanisms Patterns of LA toxicity Summary

15. Patterns of LA toxicity CV system CNS Allergy Treatment

16. Multiple LA actions on the cardiovascular system Electrophysiologic Bupivacaine vs. lidocaine: faster binding, delayed unbinding from cardiac Na channels Antiarrhythmic and proarrhythmic effects Inhibit conduction system Negative inotropic Vascular Vasoconstrict (low concentrations) Vasodilate (high concentrations) LA in CNS can have CV results Interfere with resuscitation

17. LA blood concentrations producing cardiac arrest in dogs: similar rank order as for potency

18. Ventricular arrhythmias after supraconvulsant (2x) doses of LAs

19. LA infusions, cardiac arrest & resuscitation in dogs More inducible arrhythmias with B, LB than R, Li More epi-induced VF (EpVF) & death with B than R or Li Continued epi often needed for Li (86%) after arrest; rarely with B

20. Bupivacaine more toxic thanlevo or ropivacaine in rats Rats infused LA at 2 mg/kg/min Asystole treated with epi .01 mg/kg + CPR Resuscitation success: SAP >100 mmHg B more potent than LB or R at sz, arr, asystole Less epi needed for ropiv than bup or levo

21. Is there one common mechanism for LA-induced cardiac death? Arrhythmias (bupivacaine)? Left-ventricular depression (lidocaine)? Resuscitation drug failure (bupivacaine)? Mechanism probably depends on specific drug!

22. CNS toxicity from LAs Progression of signs & symptoms with ?LA Vertigo Tinnitus Ominous feelings Circumoral numbness Garrulousness Tremors Myoclonic jerks Convulsions CNS depression Convulsive LA dose inversely related to LA potency Acidosis, hypercarbia ? convulsive dose Pregnancy lowers dose but not concentration producing convulsions CV toxicity requires greater LA doses and concentrations than CNS toxicity

23. CNS toxicity from LAs Progression of signs & symptoms with ?LA Vertigo Tinnitus Ominous feelings Circumoral numbness Garrulousness Tremors Myoclonic jerks Convulsions CNS depression Convulsive LA dose inversely related to LA potency Acidosis, hypercarbia ? convulsive dose Pregnancy lowers dose but not concentration producing convulsions CV toxicity requires greater LA doses and concentrations than CNS toxicity

24. LA doses and blood concentrations producing convulsions in sheep: similar rank order as for potency

25. Allergy to LAs Common misdiagnosis after accidental IV injections True allergy more common with esters (particularly those related to PABA) than amides Avoid PABA in sunscreens Possible cross reaction between PABA and methylparaben (preservative in some amide LAs)

26. None of 90 patients referred for LA reactions have allergy! 0 of 90 reacted to 1:100 LA dilutions! Few respond to undiluted LA even among 14 referred after anaphylactoid reactions Thus, almost no patients had �real� LA allergy

27. Treatment of local anesthetic toxicity Apparent allergy Steroids Histamine (H1) blockers With severe reactions Intravenous fluid Epinephrine CNS toxicity Don�t treat minor reactions Seizures: maintain airway, provide O2 Terminate seizure with thiopental, midazolam, or propofol Intubate patients with full stomachs

28. Treatment of local anesthetic toxicity Apparent allergy Steroids Histamine (H1) blockers With severe reactions Intravenous fluid Epinephrine CNS toxicity Don�t treat minor reactions Seizures: maintain airway, provide O2 Terminate seizure with thiopental, midazolam, or propofol Intubate patients with full stomachs

34. Local anestheticsystemic toxicity History Mechanisms Patterns of LA toxicity Summary

35. Summary LAs are not discriminating in selecting binding sites CV toxicity Electrophysiology vs inotropy Specific agent CNS toxicity Allergy: a rare event Resuscitation: we await the first reported use of lipid for resuscitation of a human

37. Local anestheticsystemic toxicity John Butterworth, MD Professor & Head Section on Cardiothoracic Anesthesiology Wake Forest University School of Medicine Winston-Salem, North Carolina