Miracle Cure? 1: Lipid Rescue® for Local Anesthetic Toxicity

1
Miracle Cure? 1Lipid 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 80s 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

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)

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

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Stay out of trouble2

• Potency
• Ropiv lt Bupiv
• CV toxicity Ropiv lt Bupiv
• Animal studies appear to suggest dose to induce
  CV toxicity
• Ropiv dose approx twice Bupiv dose

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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

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Perceived MOA

• 2 theories5
• 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

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

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?

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Compared to standard resuscitation6

• Weinberg Lipid vs. Epinephrine vs. saline6
• Rats, Bupiv 20 mg/kg ? asystole
• Lipid 5 ml/kg 0.5 ml/kg/min
• Epi 30 µg/kg
• Doses repeated _at_ 2.5 5
• ROSC _at_ 10
• Lipid 5/5
• Epi 4/5
• Ctrl 2/5

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Compared to standard resuscitation6

• Weinberg Lipid vs. Epinephrine vs. saline6
• Rats, Bupiv 20 mg/kg ? asystole
• Lipid 5 ml/kg 0.5 ml/kg/min
• Epi 30 µg/kg
• Doses repeated _at_ 2.5 5
• ROSC _at_ 10
• Lipid 5/5
• Epi 4/5
• Ctrl 2/5

13
Lipids dont help ACLS9

• Hicks (2009) swine model
• Bupivacaine 10 mg/kg
• CPR x 5
• EPI 100 µg/kg vasopressin 1.5 units/kg
• EPI 15 every 3
• If no ROSC _at_ 20
• Intralipids 20 4 ml/kg
• Intralipids did not improve rates of ROSC

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Cause you give too much EPI8

• Hillers (2009) rat model
• Received bupivacaine 20 mg/kg,
• CPR x 3
• Saline control
• Intralipid control 30, 5ml/kg (_at_ 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)

15
Hiller (2009)8
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You pigs

• Bushey et al (2011)12
• Swine with bupivacaine hypoxic arrest
• ACLS, 12 per group (lipids vs saline)
• Intralipids 4 ml/kg infusion _at_ 4.25 mark
• Outcome
• ROSC control 4, lipid 6
• pH _at_ 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 gtgt 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

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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

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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
• www.lipidrescue.org

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Courtesy K. McCully, CRNA
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References

• Herlocker, T. Wedel, D. (2002). Local
  Anesthetic ToxicityDoes Product Labeling Reflect
  Actual Risk? Regional Anesthesia and Pain
  Medicine, 27 (6)562567.
• Leone, S. et al (2008). Pharmacology, toxicology,
  and clinical use of new long acting local
  anesthetics, ropivacaine and levobupivacaine.
  ACTA BIOMED 79 92-105.
• Weinberg G, et al (2003). Lipid emulsion infusion
  rescues dogs from bupivacaine-induced cardiac
  toxicity. Reg Anesth Pain Med28198202.
• 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, 61107109.
• Weinberg GL et al (2008). Resuscitation with
  lipid versus epinephrine in a rat model of
  bupivacaine overdose. Anesthesiology,
  108(5)907-13.
• 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, 14105-11.
• Hiller, D et al (2009). Epinephrine Impairs Lipid
  Resuscitation from Bupivacaine Overdose.
  Anesthesiology, 111(3)498-505.
• 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)138-146.
• 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)140-144.
• Neal, J et al (2010). Local Anesthetic Systemic
  Toxicity 2010. Regional Anesthesia Pain
  Medicine, 35(2)152-193.
• 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)
  129-138.