Local Anesthe c Toxicity and Nerve Injury

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Disclosures Local Anesthec Toxicity and Nerve Injury David B.

Scenario Clinical Scenario 24 y/o healthy male presents for ORIF

5% bupivacine injected for supraclavicular nerve blockade <1 minute

clonic seizures Apnea, ventricular fibrillaon Chest compressions,

al, RAPM 2008 Evaluaon from 1980 2000 Peripheral nerve blocks were

1 Disclosures Local Anesthec Toxicity and Nerve Injury David B. Auyong, MD Virginia Mason Medical Center Seale, WA Clinical Scenario Clinical Scenario 24 y/o healthy male presents for ORIF radius and ulna 30mL 0.5% bupivacine injected for supraclavicular nerve blockade <1 minute aer compleon of injecon, loss of consciousness followed by tonic- clonic seizures Apnea, ventricular fibrillaon Chest compressions, epinephrine, ACLS Closed Claims and Peripheral Nerve Blocks Lee et al, RAPM 2008 Evaluaon from Peripheral nerve blocks were primarily associated with temporary injuries Local Anesthec Toxicity was associated with 7 / 19 claims with death and brain damage 1

$1887, Mason reviewed 50 cases of cocaine toxaemia These cases associated with respiratory depression, seizures, cardiac distress Recommended fraconated injecon and idenfied the need to have$ local anesthec toxicity Dr.

2 1887, Mason reviewed 50 cases of cocaine toxaemia These cases associated with respiratory depression, seizures, cardiac distress Recommended fraconated injecon and idenfied the need to have resuscitaon drugs immediately available History of Cocaine Lipid Rescue Guy Weinberg, intrigued by a case of cardiotoxicity from 22mg bupivacaine hypothesized that carnine deficiency led to enhanced local anesthec toxicity Dr. Weinberg hypothesized that because bupivacaine inhibits carnine acylcarnine translocase, the addion of lipid (which also inhibits this enzyme) would potenate toxicity Lipid Rescue Weinberg et al, Anesthesiology 2000; 92(2) Guy Weinberg, intrigued by a case of cardiotoxicity from 22mg bupivacaine hypothesized that carnine deficiency led to enhanced local anesthec toxicity Dr. Weinberg hypothesized that because bupivacaine inhibits carnine acylcarnine translocase, the addion of lipid (which also inhibits this enzyme) would potenate toxicity Rats were pre- treated with saline or lipid Infusion of 0.75% bupivacaine to asystole Dose response Increased LD 50 of bupivacaine 48% RAPM 2003; 28: LIPID EMULSIONS INCREASE THE LD 50 OF BUPIVACAINE IN SMALL ANIMALS LIPID EMULSIONS INCREASE SURVIVAL AFTER TOXIC DOSES OF BUPIVACAINE IN DOGS Video courtesy Dr. Guy Weinberg 2

levels, higher venous saturaon CONCLUSION: Lipid provides superior hemodynamic and metabolic recovery from bupivacaine- induced cardiac arrest than do vasopressors Di Gregorio et al, Crit Care Med

3 Lipid vs Standard Resuscitaon WHAT OTHER RESUSCITATION MEDICATIONS SHOULD BE USED WITH LIPID? Study resuscitang rats with either lipid, vasopressin, or vasopressin +epinephrine Lipid showed improved spontaneous return of circulaon, progressive increase of systolic pressure, lower lactate levels, higher venous saturaon CONCLUSION: Lipid provides superior hemodynamic and metabolic recovery from bupivacaine- induced cardiac arrest than do vasopressors Di Gregorio et al, Crit Care Med 2009; 37; Lipid vs Standard Resuscitaon Lipid LIPID THERAPY SHOWS IMPROVED OUTCOMES COMPARED TO EPINEPHRINE OR VASOPRESSIN IN ANIMAL MODELS OF TOXICITY Epi Vasopressin LOW DOSE EPINEPHRINE MAY HAVE SOME BENEFIT BUT VASOPRESSIN IS LIKELY HARMFUL Courtesy of Dr. Guy Weinberg Does lipid work for all local anesthecs? Zausig et al, Anesth Analg 2009; Isolated rat hearts given LA to arrest Bupi-, ropi-, mepi- vacaine Lipid followed Conclusion: Lipid rescue works best for highly lipid soluble drugs (bupivacaine) Lipid solubility of local anesthecs Bupivacaine [butylic C 4 H 9 ] Lipid/H20 paron coefficient = 27.5 Ropivacaine [propylic C 3 H 7 ] Lipid/H20 paron coefficient = 2.8 Mepivacaine [methylic CH 3 ] Lipid/H20 paron coefficient = 0.8 Lipid solubility, analgesic potency, toxicity = bupivacaine > ropivacaine > mepivacaine 3

4 Rats given infusions of varying lipid loads, 20% lipid Dixon up- down methodology LD50 = 67 ml/kg Microscopic abnormalies were found in lung and liver at doses >60 mg/kg Reg Anesth Pain Med 2010;35: EXPERIMENTALLY, LIPID IS MOST EFFECTIVE WITH BUPIVACAINE TOXICITY CLINICALLY, LIPID HAS REVERSED MULTIPLE TYPES OF LOCAL ANESTHETIC TOXICITY AT RECOMMENDED DOSING, LIPID EMULSIONS ARE UNLIKELY TO CAUSE HARM 4

Atlanta Child, 5, Dies From Local Anesthesia June 2011 What local anesthec drug doses should we be using?

of injecon, age, or renal/hepac/cardiac dysfuncon Affect blood levels and clearance» Rosenberg, et al.

(200 mg*) (400 150 mg 100 mg (epidural) 150 mg 175 mg mg/24 h) With epi 175 mg 150 mg 150 mg 225 mg Levobupivacaine 150 mg (400 mg/24 h) 150 mg 150 mg 150 mg With epi Lidocaine 200 mg 200 mg 200 mg

5 Atlanta Child, 5, Dies From Local Anesthesia June 2011 What local anesthec drug doses should we be using? Recommendaons for maximum doses of LA are NOT evidence based Grade C (case series or poor quality cohort) Historically, maximum doses have been a total amount for a drug Do not take into account site of injecon, age, or renal/hepac/cardiac dysfuncon Affect blood levels and clearance» Rosenberg, et al. Reg Anesth and Pain 2004; 29: Finland Germany Japan Sweden US 2-Chloroprocaine 800 mg With epi 1,000 mg 1,000 mg Procaine 500 mg 600 mg (epidural) 500 mg With epi 600 mg Bupivacaine 175 mg (200 mg*) ( mg 100 mg (epidural) 150 mg 175 mg mg/24 h) With epi 175 mg 150 mg 150 mg 225 mg Levobupivacaine 150 mg (400 mg/24 h) 150 mg 150 mg 150 mg With epi Lidocaine 200 mg 200 mg 200 mg 200 mg 300 mg With epi 500 mg 500 mg 500 mg 500 mg Mepivacaine 300 mg 400 mg (epidural) 350 mg 400 mg With epi 500 mg 350 mg 550 mg Prilocaine 400 mg 400 mg With epi 600 mg 600 mg 225 mg (300 mg*) ( mg (epidural) 300 mg Ropivacaine No mention 225 mg 225 mg (300mg*) mg/24 h) (infiltr.) mg/kg dosing (-) Epi (+) Epi Lido 5 mg/kg 7 mg/kg Mepiv 5mg/kg 6mg/kg Bupiv 2.5 mg/kg 3 mg/kg Ropiv 2.5 mg/kg 3 mg/kg Epinephrine 1:400,000 (2.5mcg/ml) can slow the systemic uptake and peak blood levels of local anesthec aer bolus injecon With epi 225 mg No mention 225 mg 225 mg (300mg*) Ropivacaine plasma concentrations after infusions Brodner et al 2007 A&A Bleckner et al 2010 A&A Local Anesthec Toxicity Airway support, avoid hypoxia and acidosis Benzodiazepines Avoid propofol, vasopressin ACLS Chest compressions Small doses of epinephrine (<1mg) Lipid 20% 1.5mL/kg 20% lipid emulsion bolus 0.25mL/kg/min infusion, connue even aer improvement Maximum of 10mL/kg over 30 minutes (OK to repeat bolus 1-2x) Cardiopulmonary bypass Neal et al, ASRA Pracce Advisory, RAPM 2010;35:

ASRA ASRA Checklist 2012 Epinephrine Dosing: 1:400,000 (2.

anesthec around the nerve by decreasing clearance* *Bernards and Kopacz, Anesthesiology 1999 Epinephrine # Nerve Injury Clinical Effects:

Potenates local anesthec toxicity Clinical risk is minimal in normal nerves Consider decreasing dose if potenal for pre- exisng nerve injury

Neuropraxia Damage to the myelin sheath which disrupt the acon potenal As the axon is intact, the myelin sheath can be repaired Beer

6 ASRA ASRA Checklist 2012 Epinephrine Dosing: 1:400,000 (2.5mcg/mL) adults 1:200,000 (5mcg/mL) pediatrics Clinical Effects: Decreases peripheral nerve blood flow Increases concentraon of local anesthec around the nerve by decreasing clearance* *Bernards and Kopacz, Anesthesiology 1999 Epinephrine # Nerve Injury Clinical Effects: Increases block duraon for lidocaine, mepivacaine, and bupivacaine (2-6 hours) Does not increase duraon of ropivacaine Nerve Injury: Potenates local anesthec toxicity Clinical risk is minimal in normal nerves Consider decreasing dose if potenal for pre- exisng nerve injury (diabec, chemotherapy, atherosclerosis) # Levy et al, Plast Reconstr Surg 2003 Nerve Injury Ultrasound Can Detect Intraneural Injecon Neuropraxia Damage to the myelin sheath which disrupt the acon potenal As the axon is intact, the myelin sheath can be repaired Beer prognosis and faster resoluon Examples: compression, stretch injury Axonal Loss Axon is destroyed Recovery dependent on collateral reinnervaon or axonal regrowth Slow, incomplete recovery Examples: blunt trauma, ischemic Bicpes Fem P T Semi- membranosus 6

Ultrasound Can Detect Intraneural Injecon Ultrasound Can t Keep Anesthesiologists from performing Intraneural Injecons

Intraneural Needle Placement Cadaver model of human sciac nerve 10 needle punctures (blunt and sharp needles) were evaluated

9%) Conclusion: Intraneural needle placement usually results in needles passing around the fascicles, not through them Sala-

needle placement A minimum smulang current is not a reliable marker of intraneural needle placement.

review of Injecon pressure shows: Injecon Pressure Monitoring for high injecon pressure seems neither sensive nor specific

including fascial layers, tendon, or compressed ssues Low pressure injecons have caused histologic injury in animal models

7 Ultrasound Can Detect Intraneural Injecon Ultrasound Can t Keep Anesthesiologists from performing Intraneural Injecons Intenonally Biceps brachii MC Coracobrachialis A Anesthesiology 2009; 110(6): Intraneural Needle Placement Cadaver model of human sciac nerve 10 needle punctures (blunt and sharp needles) were evaluated microscopically 4/134 fascicles were damaged (3.4%) 1/112 vessels were damaged (0.9%) Conclusion: Intraneural needle placement usually results in needles passing around the fascicles, not through them Sala- Blanch 2009 RAPM Nerve Smulaon A review of nerve smulaon alone shows: Needle- nerve distance is not reliably reflected Intraneural vs. Extraneural needle p locaon cannot be disnguished reliably Does not prevent needle- nerve contact Does not prevent intraneural needle placement A minimum smulang current is not a reliable marker of intraneural needle placement. There is no agreed upon minimum smulang current for intraneural p locaon (compared to extraneural) Macfarlane RAPM 2011 A review of Injecon pressure shows: Injecon Pressure Monitoring for high injecon pressure seems neither sensive nor specific enough to reliably detect intraneural / intrafascicular needle placement There are many causes for high injecon pressure including fascial layers, tendon, or compressed ssues Low pressure injecons have caused histologic injury in animal models Ultrasound A review of ultrasound shows: Using ultrasound to detect nerve expansion suggests intraneural injecon has already occurred Ultrasound resoluon is not adequate to disnguish intraneural from intrafascicular injecon Ultrasound can detect very small volumes of intraneural injectate but the clinical significance of this has yet to be studied Macfarlane RAPM 2011 Macfarlane RAPM

Evidence: Ultrasound and Nerve Injury Intraneural injecon (sub- epineurium) has been correlated with histologic injury but not clinical injury Lupu et al, RAPM 2009; Bigeleisen et al, Anesthesiology

RAPM 2008 Barrington et al, RAPM 2009; Liu et al, RAPM 2009; Abrahams et al, BJA 2009 Permanent nerve injury is so rare (0-4/10,000) it is impossible to study in a randomized fashion Pediatric

sedaon 88% ultrasound use 0 complicaons reported Stascal Incidence of complicaons: 0-7.

shaped tourniquets use less pressure to occlude blood flow Tourniquet Pressure: Should be set to limb occusion pressure + 40-60mmHg Duraon of use: 2 hours is considered to be safe; >3 hours is

8 Evidence: Ultrasound and Nerve Injury Intraneural injecon (sub- epineurium) has been correlated with histologic injury but not clinical injury Lupu et al, RAPM 2009; Bigeleisen et al, Anesthesiology 2006; Hara et al RAPM 2012 Underpowered results from RCTs and large case series show no difference in nerve injury when comparing localizaon technique Asleep/Heavy sedaon vs Awake Bernards et al, RAPM 2008 Barrington et al, RAPM 2009; Liu et al, RAPM 2009; Abrahams et al, BJA 2009 Permanent nerve injury is so rare (0-4/10,000) it is impossible to study in a randomized fashion Pediatric Regional Anesthesia Network (PRAN) Evaluated interscalene blocks for LAST (Local anesthec systemic toxicity) and PONS (Post- op neurologic symptoms) 518 blocks idenfied: 390 under GA, 123 under sedaon 88% ultrasound use 0 complicaons reported Stascal Incidence of complicaons: 0-7.7/1000 Trauma Nerve Injuries: Mechanism of Acon Nerve Injuries: Mechanism of Acon Compressive injury Ischemia From Tourniquet Nerve Injuries and Tourniquets Tourniquet Design: Wider, cylindrical shaped tourniquets use less pressure to occlude blood flow Tourniquet Pressure: Should be set to limb occusion pressure mmHg Duraon of use: 2 hours is considered to be safe; >3 hours is concerning. Tourniquet inflaon/deflaon: Limited evidence for benefit if total me is less than 3 hours. It is unknown what is the best duraon to leave cuff down before re- inflang (most range from 3-20 minutes) CONCLUSION: Higher levels of tourniquet pressure and higher pressure gradients beneath tourniquet cuffs are associated with a higher risk of nerve- related injury Noordin et al J Bone Joint Surg Am. 2009;91:

Double- Crush Injury Pre- exisng Nerve Damage Pre- exisng peripheral neuropathy: No real evidence to support the double- crush theory. However, careful risk/benefit assessment should be considered.

If the paent has a mass lesion of the spinal canal or severe spinal stenosis, care should be exercised with high volume anesthecs (epidurals) In paents with pre- exisng neurologic deficits consider:

Nerve Injury Evaluate: Intensity and duraon of symptoms Complete or progressive neural deficits should prompt urgent evaluaon by a neurologist Mild (ngling) and/or resolving symptoms indicate

9 Double- Crush Injury Pre- exisng Nerve Damage Pre- exisng peripheral neuropathy: No real evidence to support the double- crush theory. However, careful risk/benefit assessment should be considered. Pre- exisng CNS disorders: No evidence links neuraxial anesthesia worsened outcomes with CNS disorders (e.g, MS), but assess risk/benefit of the procedure. If the paent has a mass lesion of the spinal canal or severe spinal stenosis, care should be exercised with high volume anesthecs (epidurals) In paents with pre- exisng neurologic deficits consider: lower dose/concentraon/volume of local anesthecs, and using a lower concentraon of vasoconstricve addives RAPM (5) Regional Anesthesia with Pre- exisng Disease Diagnosis of Peripheral Nerve Injury Evaluate: Intensity and duraon of symptoms Complete or progressive neural deficits should prompt urgent evaluaon by a neurologist Mild (ngling) and/or resolving symptoms indicate excellent prognosis If symptoms fail to improve, neurological consultaon should be sought within 2-3 weeks Consider MRI or nerve conducon studies Motor compromise more worrisome than sensory ASRA Guidelines 2008 Diagnosis of Peripheral Nerve Injury Nerve conducon studies / EMG Can give quantave evaluaon of nerve funcon Can assist in giving a beer idea of prognosis Early EMG is less informave about the injury compared to EMG at 2-3 weeks as impairment evolves over me Early EMG can establish if the nerve has injury at baseline prior to the current insult MRI preferred over CT MRI is beer at evaluaon of nerves and so ssue structures Sorenson RAPM

Diagnosis / Treatment Guidelines: Peripheral Barrington et al RAPM

the Paent Communicate Do Not Place Blame Referral as needed Keep in

Summary of Suspected Nerve Injury Nerve injuries are rare but can

Urgent consult to neurology / neurosurgery for suspected neuraxial

10 Diagnosis / Treatment Guidelines: Peripheral Barrington et al RAPM 2009 ASRA Guidelines 2008 Document well Gerancher RAPM 2005 Care of the Paent Communicate Do Not Place Blame Referral as needed Keep in contact with paent Documentaon of connued interacons with paent Summary of Suspected Nerve Injury Nerve injuries are rare but can be significant Most cases will improve and resolve without deficit Urgent consult to neurology / neurosurgery for suspected neuraxial compromise or peripheral sensorimotor deficits that are severe /complete 10

Prevention and Treatment Patrick Levelle, MD

Prevention and Treatment Patrick Levelle, MD LOCAL ANESTHETIC TOXICITY 1. PERIPHERAL NERVE BLOCKS 2. ROLE OF THE PERIANESTHESIA RN 3. LOCAL ANESTHETIC TOXICITY Use of Lipid Emulsion Regional and Peripheral