1. Miracle Cure? #1: Lipid Rescue® for Local Anesthetic Toxicity
Joe Dietrick, CRNA, M.A.
Truman Medical Center
Kansas City, MO

2. Objectives
Review history of cardiovascular collapse with local anesthetics
Discuss effect of local anesthetic toxicity on myocardial function
Discuss treatment options, focusing on infusion of Intralipids®

3. History of the world… Anesthesia for CS Epidurals in 70 – 80’s 1
Short-acting  Bupivacaine 0.5 – 0.75%
1979: CV collapse with etidocaine/bupivacaine
Difficult (impossible) prolonged resuscitation
1983: 59 cardiac (35 OB) cases
39 Epidurals, 27 used Bupiv 0.75%
31 deaths (24 mother &/or baby)
83% of LA toxicity  neurologic injury / death
FDA: Bupiv 0.75% not recommended for OB
According to Joe
1979: Albright published reports start of inadvertent IV injection, with CV collapse before CNS S/S
CV before CNS assumed to not commonly occur
1983 FDA convened a meeting
83%: Closed claims data from early 80’s
Incr sensitivity in pregnancy

4. History of the world… Part II
Early ’90s
Pencil point spinal needles   SAB for CS
 epidural injection of high concentration LA
Late ’90s
Ropivacaine approved for general use
Generally 30% improvement in safety margin
Max concentration for OB: 0.5% (150 mg)
My anesthesia school – grad rate
Ropiv: S enantomer  less CV & CNS toxicity

5. CV Toxicity2 Act on Na+ channel inside cell
Reversible nerve conduction block
CNS: most susceptible to toxic effects
CV effects
 cardiac conduction   PR, QRS
Inhibition of K+ channel   QTc
Dextrorotary   K+ blk
Highly selective for vascular K-ATP channels
Bupiv dissociation 10x longer vs. Lido
Dex 7x greater blk than Levo
K-ATP – (ATP-sensitive K+ channels) Bupiv greater effect than Levo or Ropiv
Ischemic heart disease may be more susceptible as well
Racemic

6. Stay out of trouble2 Potency CV toxicity: Ropiv < Bupiv
Animal studies appear to suggest dose to induce CV toxicity:
Ropiv dose approx twice Bupiv dose
Epidural Equipotency LA
Surg
Post-Op
Ropiv
0.75%
0.2%
Bupiv
0.5%
0.125%
One source recommended 300mg max (CJA 2005, 52:449)
Fatal dose in sheep: Bupiv about 3.5 mg/kg, Ropiv about 7.3 mg/kg (AA :276)
Anecdotal report: Bupiv 1.1 mg/kg  Cv arrest (CJCP , 3:240

7. What Weinberg says.
Incidentally found lipid emulsion reversed LA-induced cardiac arrest
2003 report with dogs, Bupiv 10 mg/kg3
10’ CPR
Lipid 20% 4 ml/kg vs NS
Survival
TX: 6/6
Ctrl: 0/6
Dogs under GA, actually second study
Fat is good for you??

8. Perceived MOA 2 theories5 Bupiv effect on myocardial acidosis4
Fat sink  reverse [gradient] for lipophilics
LA inhibits FA entry to mitochondria
Bupiv effect on myocardial acidosis4
Bupiv or NS injected, then VF induced
Monitored 20’ or pHm = 7.0
Bupiv  Intralipid; both groups defibrillated
Bupiv group had less myocardial acidosis
“inhibition of cellular metabolism”
Myocardium primarily uses FA metabolism for energy (vs carbs). No FA in Mito  no ATP diff resusc?
Mazoit 2009 anesthesiology: compared 2 lipids (intralipids – long chain, vs med & long chain) : Intraliipid – more efficacious.
Weinberg (2004): Dogs anesthetized, given saline or bupiv 10 mg/kg, and VF induced (9v battery to epicardium)
Not a test of Intralipids; NS group responded to defib w/o addt’l tx
Actual final comment: consider treating VF with Bupiv followed by lipids

9. Really? www.lipidrescue.org Lists studies & case reports
Published (17)
Submitted case reports (a bunch)
Recommends standard resuscitation, then
Intralipid® 20%
1.5 ml/kg bolus, MR for persistent asystole
0.25 ml/kg/min for 30-60’
“Not a diet website”
Does this really work?
Successful resus from CV collapse or significant distress
All published reports.
Volume based (ml/kg) dose
Off label: well informed, scientific rationale, maintain records

10. ACLS is da’ bomb – or it bombs
Ropivacaine & Levobupivacaine have had successful standard resuscitations
Anesthesiology: Mar 2007
Mult letters regarding Rosenblatt case report
ROSC immed after lipid, but 20’ of conventional management could have contributed
c/o shocking asystole
c/o global term “LA toxicity” vs racemic Bupiv, and ? CNS efficacy
“Failure to ventilate & maintain cardiac perfusion?”
CNS: efficacy in CNS toxic events
Mult Letters: 1) stated that even though ROSC immed after lipids & 20’ after arrest, stand resusc could have contributed 2) complained about shocking asystole (?), 3) c/o global term LA vs racemic bupiv (subseq case studies have proven efficacy), 4)

11. Compared to standard resuscitation6
Weinberg: Lipid vs. Epinephrine vs. saline6
Rats, Bupiv 20 mg/kg  asystole
Lipid: 5 ml/kg ml/kg/min
Epi: 30 μg/kg
Doses 2.5’ & 5’
10’
Lipid 5/5
Epi 4/5
Ctrl 2/5
Weinberg
Lipid: 5 ml/kg ml/kg/min
Epi: 30 μg/kg
Doses 2.5’ & 5’
RPP non-invasive indicator of O2 requirements

12. Compared to standard resuscitation6
Weinberg: Lipid vs. Epinephrine vs. saline6
Rats, Bupiv 20 mg/kg  asystole
Lipid: 5 ml/kg ml/kg/min
Epi: 30 μg/kg
Doses 2.5’ & 5’
10’
Lipid 5/5
Epi 4/5
Ctrl 2/5 NS
EPI
Lipid
Slower, but better sustained RPP

13. Lipids don’t help ACLS9 Hicks (2009) swine model If no ROSC @ 20’
Bupivacaine 10 mg/kg
CPR x 5’
EPI 100 μg/kg + vasopressin 1.5 units/kg
EPI 15 every 3’
If no 20’
Intralipids 20% 4 ml/kg
Intralipids did not improve rates of ROSC
Epi repeated q 15 mcg/kg
About 1/3 in each arm had ROSC before 20%
Interestingly, lipid group had 65% higher bupiv 10’

14. ‘Cause you give too much EPI8
Hiller’s (2009) rat model
Received bupivacaine 20 mg/kg,
CPR x 3’
Saline control
Intralipid control: 30%, 5ml/kg 2 & 5’)
Compared escalating doses of EPI
All with Intralipid treatment
μg/kg: 0, 1, 2.5, 10, 25
ROSC among all animals in a group
Lipid + Epi (1 or 2.5 μg/kg)
Dose produced asystole
Lipid: Infusion of 1 ml/kg between boluses
Epi with 1st Lipid bolus
High dose groups: incr lactate, acidosis; decr recovery

15. Hiller (2009)8
Mirrored Weinberg’s results of slower but sustained response vs epi

16. You pigs… Bushey et al (2011)12 Outcome
Swine with bupivacaine & hypoxic arrest
ACLS, 12 per group (lipids vs saline)
Intralipids 4 ml/kg ’ mark
Outcome
ROSC: control = 4, lipid = 6
4.25’: 7.33 (both groups)
Success in animals other than pigs
Pigs closer to humans

17. Risk?5 Pulmonary vasoconstriction? Editorial opinion by Picard & Meek:
Animal studies: benefit >> risk
Brull (2008): poss allergic rxn,  ICP
Imprudent to withhold in toxic events
Marwick (2009) reported recurrence
Bupiv brach plexus blk  asystole
40’ after termination of lipid  VT
Recommend 1000 ml available
P&M (2006) (British) Anaesthesia
Marwick: recovery in 3’
Brull: risk of allergic rx or incr ICP in traumatic injury
Marwick: Lipid 20% 150 ml bolus, then 350 ml /30’

18. Risk – push the limit10 Intralipids 20%
20, 40, 60, or 80 ml/kg
Rats euthanized & histologically examined
Estimated LD50 = 67 (±10.7) ml/kg
Lung & liver microscropic ∆
NL: Myocardium, brain, pancreas, & kidney
Safe at doses used

19. And all this means
If you use cardiotoxic doses (volume blocks) of any local anesthetic
Have a plan
Have Intralipid® emulsion available
Have administration instructions
Package these together
Consider in other lipid-soluble drug toxicities
MH-type preparedness
Min 500ml. ?1000ml

20. Courtesy:
K. McCully, CRNA

21. References
Herlocker, T. & Wedel, D. (2002). Local Anesthetic Toxicity—Does Product Labeling Reflect Actual Risk? Regional Anesthesia and Pain Medicine, 27 (6):562–567.
Leone, S. et al (2008). Pharmacology, toxicology, and clinical use of new long acting local anesthetics, ropivacaine and levobupivacaine. ACTA BIOMED 79:
Weinberg G, et al (2003). Lipid emulsion infusion rescues dogs from bupivacaine-induced cardiac toxicity. Reg Anesth Pain Med;28:198–202.
Weinberg G, et al (2004). The effect of bupivacaine on myocardial tissue hypoxia and acidosis during ventricular fibrillation. Anesth Analg. 98(3):790-5.
Picard, J. & Meek, T. (2006). Lipid emulsion to treat overdose of local anaesthetic: the gift of the glob. Anaesthesia, 61:107–109.
Weinberg GL et al (2008). Resuscitation with lipid versus epinephrine in a rat model of bupivacaine overdose. Anesthesiology, 108(5):
Bania T, et al (2007). Hemodynamic effects of intravenous fat emulsion in an animal model of verapamil toxicity resuscitated with atropine, calcium and saline. Acad. Emerg. Med, 14:
Hiller, D et al (2009). Epinephrine Impairs Lipid Resuscitation from Bupivacaine Overdose. Anesthesiology, 111(3):
Hicks, S et al(2009). Lipid Emulsion Combined with Epinephrine and Vasopressin Does Not Improve Survival in a Swine Model of Bupivacaine-induced Cardiac Arrest. Anesthesiology, 111(1):
Hiller, D et al. (2010). Safety of high volume lipid emulsion infusion: a first approximation of LD%) in rats. Regional Anesthesia & Pain Medicine, 35(2):
Neal, J et al (2010). Local Anesthetic Systemic Toxicity Regional Anesthesia & Pain Medicine, 35(2):
Bushey, B et al (2011). Combined Lipid Emulsion and ACLS Resuscitation Following Bupivacaine- and Hypoxia-Induced Cardiovascular Collapse in Unanesthetized Swine. AANA Journal, 79(2):