Local Anesthetic Toxicity: A Comprehensive Review In Eight Minutes

February 20, 2008 Matt Springs, MD Advisor: Jason Taylor, MD

Signs and Symptoms of Local Anesthetic Toxicity: CNS

Early signs: circumoral numbness (earliest), tongue paresthesia, dizziness Excitatory signs such as restlessness and agitation often precede CNS depression (slurred speech, drowsiness, unconsciousness) Muscle twitching heralds the onset of tonicclonic szs Respiratory arrest often follows Treat with benzos, hyperventilation (CBF), thiopental (1-2mg/kg), and oxygenation

Signs and Symptoms of Local Anesthetic Toxicity: Respiratory

Local anesthetics depress hypoxic drive (the ventilatory response to low PaO2 ) Apnea can result from phrenic and intercostal nerve paralysis Tx: respiratory support as indicated

Signs and Symptoms of Local Anesthetic Toxicity: CV

In general, LAs depress myocardial automaticity (spontaneous phase IV depolarization) and reduce the refractory period This direct myocardial depression causes bradycardia, heart block (varying degrees), and hypotension which may lead to cardiac arrest The R(+) isomer of bupivacaine avidly blocks cardiac sodium channels and dissociates slowly Major CV toxicity requires about 3X the concentration required to produce szs Ropivacaine is 70% less likely to cause severe cardiac arrhythmias than bupivacaine Treat with vasopressors and ACLS protocols Lipid infusion....another topic www.lipidrescue.org

Brief History Of Local Anesthetic Maximum Dosages

The most conservative maximum dose for lidocaine relates back to work by T. Gorgh in the 1940s He recommended a max dose of 300mg to the Astra pharmaceutical company However, the company decided to use 200mg instead, which remains the max dose in most of Europe Typically, max doses have been determined by extrapolating data obtained from lab animals to man, followed by clinical investigations in man using those doses Case reports of systemic toxicity have also been used to derive max doses No human studies of max doses causing severe toxicityhowever

Volunteers Needed For Study

Study aim: To determine the exact maximum dose of bupivacaine that can be given by way of a peripheral nerve block Double-blinded RCT End pointsevere toxicity resulting in sz, cardiac arrhythmia, or death Disclaimer: Not approved by the MUSC Ethics Committee for the general public**#
**approval granted for anesthesia residents only #little to no compensation provided

Is There Room For Comfort?

In 2003, McCartney et al investigated the intravenous dose of ropivacaine which would cause mild CNS symptoms All patients tolerated ropivacaine 60mg i.v. The peak blood level was found to be 4.48ng/mL at the time of mild symptoms Also determined that up to 0.03mg/kg versed i.v. did not mask symptoms

Is There Room For Comfort?

How does 4.48ng/mL relate to us? In 2006, Vanterpool et al from Duke investigated plasma levels of ropivacaine after lumbar plexus block (35cc of 0.5% c epi) versus combined LP/sciatic (60cc of 0.5% c epi) In the twenty patients, there was no evidence of systemic effect The average Cmax for the LPSN group was 1560ng/mL, with the highest being 2345ng/mL This is essentially half of the plasma concentration shown in McCartneys study to illicit mild CNS symptoms

Patient Related Factors to Consider During Large Volume PNBs

AGE: Newborns have about half the adult concentration of 1acid glycoprotein (AAG) which binds free LAs - reduce by 15% Persons over 70 show sensitivity to LAs and decreased clearance reduce by 10-20% Renal Dysfxn: There is may or may not be a change in clearance of LA in nonuremic and uremic pts More importantly, uremic pts show a rapid rise in [LA] probably secondary to a hyperdynamic circulation ( circ = uptake) The good news uremic pts have AAG Recommendation: reduce LA bolus by 10-20% in uremic pts and reduce continuous regional anesthetic techniques by 10-20%

Patient Related Factors to Consider During Large Volume PNBs

Hepatic Dysfxn: Clearance of LA can be dramatically but plasma concentrations remain close to normal secondary to Vd These patients also can have renal and cardiac dysfxn Rec: Initial bolus can be in the normal dose range but continuous infusions should be reduced 10-50% Heart Failure: blood flow to the liver and kidneys can cause a in clearance Repeat or continuous dosing of LAs should be reduced by 10-20%

Patient Related Factors to Consider During Large Volume PNBs

Pregnancy: Progesterone may sensitivity of nerve axons There seems also to be an enhanced risk of cardiotoxicity by bupivacaine and ropivacaine in pregnancy induced by progesterone in CO causes uptake Rec: avoid large volume PNBs in 1st trimester Reduce doses in epidural and spinal anesthesia in pregnancy Drug interaction: Amides are cleared by the liver cytochrome P450 enzymes Propanolol, cimetidine and itraconazole can bupivacaine clearance by 30-35% Cipro and fluvoxamine decreased the clearance of ropivacaine Rec: single shots are of little concern but continuous infusions should be altered (10-20% decrease)

Conclusions
Severe local anesthetic toxicity is a rare but devastating side effect of LAs administration occurring in 7.5 to 20 adults per 10K blocks Know the signs and symptoms and be prepared to treat immediately Inadvertent intravascular injection is the #1 cause of toxicity at the time injection Use epinephrine when at all possible Avoid bupivacaine if possible In healthy pts, standard maximum doses are likely a very safe estimate and can probably be increased However, special consideration should be given to certain pt populations

References
McCartney, Colin J.L. et al. Intravenous ropivacaine bolus is a reliable marker of intravascular injection in premedicated healthy volunteers. Can J Anesth 2003; 50:795-800 Morgan, G. Edward, Jr. Chapter 14, Local Anesthetics. 2006 Renehan, Elizabeth M. et al. Scavenging Nanoparticles: An Emerging Treatment for Local Anesthetic Toxicity. Regional Anesthesia and Pain Medicine 2005; 30:380-84 Rosenberg, H. MD PhD et al. Maximum Recommended Doses of Local Anesthetics: A Multifactorial Concept. Regional Anesthesia and Pain Medicine 2004; 29:564-575 Vanterpool, Stephanie et al. Combined Lumbar-Plexus and Sciatic-Nerve Blocks: An Analysis of Plasma Ropivacaine Concentrations. Regional Anesthesia and Pain Medicine 2006; 31:417-421