1. Local Anesthetics Toxicity and Management
Romanian intro
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Today I will be discussing Local Anesthetic Toxicity and its management. I have no financial interest in anything related to today’s talk. I will be presenting evidence related to the off-label use for a 20% lipid emulsion known as INTRALIPID.
I’ll cover information that will enable you to:
Recall the pharmacology of local anesthetic drugs
Effectively identify and manage adverse reactions related to the use of local anesthetics.
Review the recommended management of acute life-threatening systemic toxicity from local anesthetics.
Gregory Pate, MD Department of Anesthesia Bremerton Naval Hospital

2. Local Anesthetic Toxicity Topics
Local Anesthetic Pharmacology
Adverse Reactions to Local Anesthetics
Types of Toxicity
Acute Systemic Toxicity
Management of Acute Systemic Toxicity
Here is an overview of the topics for our discussion today. We will begin with 2 slides reviewing the pharmacology of local anesthetics… followed by a look at problems that can arise from use of local anesthetics including toxicity and recommended treatments.
Let’s get started!

3. Basics: Local Anesthetic Pharm
Amino esters and Amino amides
Metabolism
Protein binding
Lipophilic-hydrophilic balance
Hydrogen Ion concentration
Since cocaine was first isolated in 1860 by Albert Niemann, local anesthetics have been a source of innovation and advancement among medical practitioners.
To review the pharmacology… most current local anesthetics can be divided into two main categories on the basis of the structure located in the middle of the molecule. If the intermediate bond or chain in the middle between a lipophilic aromatic group on one end and a more water soluble amine group on the other is an ester, then the molecule is an Amino ester and if that middle structure is an amide the molecule is an amino amide.
Amino amides are metabolized mainly by amidase in the liver- and allergic reactions to these drugs or their metabolites are very uncommon. Amino esters, which are generally more quickly eliminated, are metabolized primarily by plasma cholinesterase. Para-aminobenzoate (PABA), a metabolite of most amino esters is associated with Type I (IgE mediated) hypersensitivity reactions.
Katzung, Basic & clinical pharm, 10th edition

4. Basics: Local Anesthetic Mechanism
Active form of the local anesthetic
Modulated receptor theory
Other possible mechanisms of action
Local anesthetics reversibly block the generation and spread of electrical impulses in electrically excitable tissue like nerves by influencing voltage-gated sodium channels.
After the non-ionized form of local anesthetic penetrates protective layers around nerve fibers, Re-equilibration of ionized to non-ionized forms occurs inside the cell. The resulting fraction of LA existing in an ionized (or active) form within the cell then binds to receptor sites within the Na+ channel.
Modulated receptor theory holds that sodium channels have specific receptor sites for local anesthetic molecules. The binding of these drugs within the voltage-gated sodium channel stops the flux of sodium ions needed for an action potential, thus preventing the generation or propagation of a nerve impulse. No action potential in nerve cells-no pain signal transmitted to the central nervous system.
Miller’s Anesthesia, 6th edition

5. Local Anesthetic Toxicity Topics
Local Anesthetic Pharmacology
Adverse Reactions to Local Anesthetics
Types of Toxicity
Acute Systemic Toxicity
Management of Acute Systemic Toxicity
There are some clinically important adverse reactions to local anesthetics worth reviewing even though they are not the result of toxicity.

6. Methemoglobinemia Prilocaine and Benzocaine
Benzocaine sprays like Cetacaine
EMLA cream which has prilocaine although this practice is still generally considered safe
Seen with use of prilocaine in epidurals around at mg for adults
Dapsone, antibiotics, nitrates, etc.
Although other drugs have been known to cause methemoglobinemia, Prilocaine and Benzocaine are the local anesthetic agents most associated with this condition. These drugs impair the ability of red blood cells to carry and release oxygen when methemoglobinemia develops.
The treatment for this condition is methelene blue 1-2 mg/kg IV. It is also good to consider that the cure-methelene blue can harm patients with G6PD deficiency and should not be given to these individuals without carefully weighing the risks. Also, the risk of rebound methemoglobinemia has been known to occur as late as 18 hours after the initial episode was successfully treated. If there is an ongoing source of the drug for absorption on skin or mucous membranes this condition can develope again.
Methemoglobin related to local anesthetics, Guay et al, 2009

7. Methemoglobinemia
Methemoglobinemia is caused by the oxidation of hemoglobin which results in a loss of it’s affinity for oxygen. This creates a functional anemia. There is always a small amount of methemoglobin in the blood (normally less than 1%) but when the level goes above 1% the diagnosis can be made. At 15% methemoglobinemia you may see skin color changes (cyanosis with blue or grayish pigmentation) and blood samples may be chocolate-brown in color like the test tube on the left in this image. Above 15%, neurologic and cardiac symptoms develop from the functional hypoxia, and levels above 70% are usually fatal.
Methemoglobin has an oxidized ferric iron (Fe 3+) rather than the reduced ferrous form (Fe 2+) found in hemoglobin. This structural change prevents methemoglobin from binding properly with oxygen. It also results in a left shift of the oxygen dissociation curve with decreased release of oxygen to tissues.

8. Hypersensitivity Reactions
IgE mediated vs Non-IgE mediated
Perioperative anaphylaxis about 1:10,000 cases-NMBD, antibiotics, latex
Does not take much allergen
True allergy to amides very rare
True allergy to esters like cocaine, procaine, chloroprocaine more common
Occurrence 1 in 10,000 anesthetic procedures but this number is probably off because anaphylaxis is under reported
In the OR the onset of anaphylaxis is most often within just a min or two of the induction of anesthesia.
While local anesthetics can cause anaphylaxis, the most common causes of these severe hypersensitivity reactions in the perioperative period are antibiotics, latex, and Neuromuscular Blocking Drugs.
Most sources mention that even a trace of the right substance can set off the cascade from mast cell mediator release
Among local anesthetics, esters are most often the cause of hypersensitivity reactions. They are metabolized to para aminobenzoic acid which is implicated in hypersensitivity. Methylparabens and other preservatives found in local anesthetics may actually be a more common cause of these reactions than the local anesthetics themselves.
Anaphylaxis and Anesthesia, Dewachter, 2009

9. Features of Anaphylaxis
Airway: stridor, hoarseness, laryngeal edema, dyspnea, cyanosis, bronchospasm, and obstruction
Cardiac: tachycardia, hypotension, arrhythmia, cardiac arrest
Neuro: dizzy, weak, syncopal, seizure
Skin: flushing, erythema, pruritis, angioedema, maculopapular rash
Review slide
I am sure everyone here is familiar with the management of anaphylaxis since it could occur anywhere in the hospital or clinic.
ABCs-airway, O2, IV access/fluids, drugs are essential
Diagnoss and Management of Anaphylaxis, CMAJ, 2003

10. Acute Anaphylaxis Diagnoss and Management of Anaphylaxis, CMAJ, 2003
This is a standard medication algorithm for anaphylaxis.
Of course, Epinephrine as needed to support circulation as well as antihistamine and steroid.
Diagnoss and Management of Anaphylaxis, CMAJ, 2003

11. Biphasic Anaphylaxis
Anaphylaxis is normally characterized by a single period of symptoms (uniphasic anaphylaxis) but 20% of cases are biphasic with resumption of anaphylaxis 1-8 hours after the initial episode
Many sources say you are not out of the woods until 24 hours after the initial episode.
This is why it is common to keep these patients under close observation for a day following the initial event even if they are hemodynamically stable after initial treatment.
Diagnoss and Management of Anaphylaxis, CMAJ, 2003

12. Local Anesthetic Toxicity Topics
Local Anesthetic Pharmacology
Adverse Reactions to Local Anesthestics
Types of Toxicity
Acute Systemic Toxicity
Management of Acute Systemic Toxicity
There are a number of ways local anesthetic toxicity can manifest.
It may be good to think in terms of toxicity that is confined to a specific area in the body such as the distribution of a discreet nerve or muscle after extravascular injection vs. systemic effects that typically began with intravascular injection.

13. Types of Local Anesthetic Toxicity
LOCALIZED TOXICITY
Neurotoxicity
Myotoxicity
SYSTEMIC TOXICITY
CNS toxicity
CVS toxicity
So what types of local anesthetic toxicity are there?
For the sake of simplification I have divided LA toxicity into Localized Toxicity and Systemic Toxicity.
Localized toxicity is confined to a specific region of the body like a peripheral nerve or a muscle following an injection that would typically be extravascular. Localized toxicity is generally not life threatening although morbidity involving nerve or muscle injury can occur.
Systemic toxicity, on the other hand, can result in dose dependent Central Nervous System or Cardiovascular toxicity with potentially devastating consequences typically following an unintentional intravascular injection.
A classic example of life threatening systemic toxicity would be the inadvertent intravascular injection of a large volume of long acting LA with indicators of CNS and CVS toxicity following an attempted Peripheral Nerve Block – towards the end of this talk we will review recommended management for this.

14. Neurotoxicity Dose/concentration Duration of nerve exposure
Most common with continuous spinal anesthesia
All amino amides/ amino esters can cause direct toxicity
Neurotoxicity is an example of LOCALIZED TOXICITY - The incidence of neurotoxicity from local anesthetics appears to be directly related to the concentration, dose, and duration of nerve exposure to local. Those factors are related to technique.
One technique we don’t use as often in the US, continuous spinal anesthesia works by infusing local via a spinal catheter for the duration of desired effect. This method has historically been associated with true neurotoxicity. In 1991, continuous spinal anesthesia was sometimes given using 5% lidocaine in a dense viscous solution infused into the intrathecal space through a small bore catheter. Case reports of cauda equina syndrome and irreversible nerve injury began cropping up from this practice. It was believed that the high concentration of the dense solution of lidocaine released from single bore microcatheters was allowing lidocaine to pool over exposed nerves that are partially unmyelinated in the cauda equina at concentrations so high it caused direct toxic injury. This exact technique is no longer practiced in the US. Although spinal catheters are regaining popularity the type of local selected and the type of catheter used has changed.
American Journal of Therapeutics, Cont Spinal Anesthesia, Moore, 2009

15. Myotoxicity Edema and necrosis after exposure to Lidocaine
Normally limited and reversible
Often reported in Ophthalmology
Myotoxicity is another example of LOCALIZED TOXICITY - This slide shows skeletal muscle after exposure to lidocaine
Since the first research on this topic in 1959 there has been evidence that local anesthetics produce myotoxicity. Skeletal muscle toxicity normally does occur to some extent with injection of local anesthetic drugs. Intramuscular injection results in reversible myonecrosis that normally resolves entirely within 2-4 weeks of injection. The extent of muscle damage is dose dependent and drug dependent.
Myotoxicity worsens with serial or continuous injection of local into muscle.
All local anesthetic agents that have been examined are myotoxic.
Zink et al., 2005

16. Prevention of LA toxicity
Dosing is a key factor in prevention
Review Therapeutic Index
Of course, the safe use of LA’s for regional anesthesia requires knowledge of proper dosing and technical skill.
To review, the therapeutic index for a drug is a ratio of the LD50 or dose lethal to 50% of population over the ED50 or minimum effective dose for 50% of the population (higher index = safer drug). The actual therapeutic index is not always easy to determine with a drug that may be injected intravascularly or extravascularly, with or without vasoconstrictors like epinephrine, and with varied rates of absorption as is the case with regional blocks.

17. Local Anesthetic Toxicity Topics
Local Anesthetic Pharmacology
Adverse Reactions to Local Anesthetics
Types of Toxicity
Acute Systemic Toxicity
Management of Acute Systemic Toxicity
Now we will review the most harm that local anesthetics have the potential to do.
Acute systemic toxicity can kill patients. This is most common with use of large volumes of the newer lipid soluble local anesthetics like bup and rop when unintentionally injected directly into a blood vessel during nerve blocks such as a block of the femoral nerve, sciatic nerve, or the brachial plexus.

18. LA toxicity - CNS
Local Anesthetics readily cross the blood-brain barrier
CNS toxicity is drug/dose dependent
Clinical indicators of CNS toxicity
Most LA drugs readily cross BBB
Effects of these drugs on the CNS are dose dependent and vary depending on the individual drug and unbound plasma concentration.
Indicators of CNS toxicity: lightheadedness, tinnitus, perioral numbness, confusion, muscle twitching, and with higher doses, hallucinations, tonic-clonic seizures, LOC, and resp arrest.
Kreitzer, Journal of Clinical Anesthesia, 1996

19. Dose Dependent Systemic Effects
Effects of Lidocaine by plasma concentration
CONC(mcg/mL) EFFECT
1– Analgesia
5– Lightheaded, Tinnitus,
Tongue numbness
10– Seizure, LOC
15– Coma, resp arrest
> CV depression
This slide provides indicators of CNS toxicity for lidocaine as a function of plasma concentration. As you can see, there is a logical progression of effect from analgesia to seizure to CVS effects.
Barash, 5th pp464

20. Relative Potency for Toxicity (CVS:CNS) Toxicity
▪AGENT
▪RELATIVE POTENCY FOR CNS TOXICITY
▪CVS:CNS
Bupivacaine 4 2
L-bupivacaine
2.9
Etidocaine
4.4
Lidocaine 1
7.1
Mepivacaine
1.4
Ropivacaine
This table is from Barash 5th.
Here we can see the first column shows relative potency for CNS toxicity with the value 1 arbitrarily assigned for lidocaine and other common LAs rated in relative terms.
The second column shows how much more drug it takes to cause CV toxicity than CNS toxicity.
Narrow margin for bup/rop compared with lidocaine.
Barash, 5th edition pp462

21. LA Toxicity - CVS
Newer amino amide local anesthetics potential to cause CNS toxicity
Indicators of CVS toxicity
Mechanism of toxicity
CVS Toxicity
From the time Dr. Albright reviewed six case reports of cardiac toxicity with the newer long-acting amide local anesthetics in 1979, it has become increasingly clear that these more potent amino amides also have a greater potential for life threatening cardiotoxicity than old standards like lidocaine.
Common indicators of cardiovascular toxicity include HTN, tachycardia, decreased contractility and CO, hypotension, sinus bradycardia, ventricular dysrhythmias, and circulatory arrest.
The mechanism of toxicity in the CVS has been a subject of much inquiry and the explanation for these undesirable effects on the heart relates back to the modulated receptor mechanism that explained the desirable effects of these drugs in peripheral nerves. Essentially, for the long acting amino amides like Bupivacaine, the CVS toxicity is a product of depressant effects on cardiac sodium channels in a time dependent manner. Time dependent because Bupivacaine has a high affinity for inactivated sodium channel receptors and rapidly blocks them but leaves the receptor slowly (fast in slow out) so as the heart rate increases, the fraction of blocked sodium channels increases as well. This results in slowed conduction of cardiac action potentials with prolonged PR interval, widened QRS, and with higher concentrations, arrhythmias or complete heart block resulting in cardiac arrest. The cardiac arrest with these drugs is often characterized in case reports as being refractory to standard ACLS measures.
Albright, Anesthesiology,1979
Clarkson, Anesthesiology, 1985

22. 30% smaller dose for Bup than others
Seizure
30% smaller dose for Bup than others
Dysrhythmia
(a) Bup 13.2 mg/kg
(b) L-Bup 43.7mg/kg
(c) Rop 91.8 mg/kg
In Shigeo’s work on systemic toxicity and resuscitation following administration of Bupivacaine, L-Bupivacaine, and Ropivacaine in rats he produced this graphic of HR and MAP as a function of time after beginning a continuous infusion of LA IV. Although this model is not the same as a onetime intravascular injection scenario it does reveal some interesting data.
As you can see, with L-Bup and Ropivacaine infusions (unfilled circle and filled circle) the rats had a period where they could still maintain a reasonable MAP from about 5 mins with onset of seizure until an abrupt drop in perfusion occurred at the points marked (a) (b) and (c) as acute bradycardia and hypotension developed with a rapid decline to asystole. By contrast with the other 2 groups, the Bupivacaine group (solid box) had a shorter period from seizure to CV collapse.
Shigeo, Anesth Analg 2001

23. EKG in CVS Toxicity Kim, Canadian J of Anesthesia, 2003
In this study from Kim done in 2003, dogs were given a Bupivacaine infusion and CV parameters were measured.
FIGURE 2 from the study is shown here with EKG tracing from lead II. The baseline at the top is compared with the “BIE” or (Bupivacaine Infusion End) tracing. In the lower tracing common changes with bupivacaine toxicity are evident. These changes include 1) Heart rate decrease BPM, 2) PR interval increase msec, 3) QRS duration prolonged msec.
The heart will sometimes develop a transient sinus tachycardia but as CVS toxicity progresses a non-perfusing tachyarrhythmia, bradycardia or asystole develops. Complete heart block has also been described.
Kim, Canadian J of Anesthesia, 2003

24. Local Anesthetic Toxicity Topics
Local Anesthetic Pharmacology
Adverse Reactions to Local Anesthetics
Types of Toxicity
Acute Systemic Toxicity
Management of Acute Systemic Toxicity
The fresh idea in treatment of life threatening acoute toxicity with local anesthetics came from Dr Guy Weinberg, an anesthesiologist at the University of Illinois
Management of acute systemic toxicity has changed for the better and has impacted the practice of every sensible person who performs regional anesthesia today

25. Early Options to Treat LA Toxicity
Epinephrine and Atropine
Shock, Shock, Shock
Other ACLS
Milrinone
Versed
Propofol
CPB
A 1979 review article on amide anesthetic toxicity noted that resuscitation from cardiovascular collapse with long acting amide local anesthetics did not look like other resuscitations. Drug and electrical therapies were often totally ineffective for long periods of time and conventional wisdom held that these resuscitations… just took longer.
The standard tools available to the clinician seemed inadequate. Although there were many cases of survival with acute systemic toxicity with very prolonged CPR or extreme measures like CPB, those were not ideal.

26. Early Options to Treat LA Toxicity Figure 1
Early Options to Treat LA Toxicity Figure 1. Lethal dose-response curves for bupivacaine in the presence or absence of verapamil and nimodipine. B = bupivacaine, N + B = nimodipine 200 [micro sign]g/kg + bupivacaine, V + B = verapamil 150 [micro sign]g/kg + bupivacaine.
Earlier efforts to investigate pharmacologic intervention in Bupivacaine toxicity included a study conducted by Adsan et all in 1998 which compared Lethal dose response curves (LD 50) in rats pretreated with calcium channel blockers. The results were disappointing with almost no improvement in survivability .
Several other studies done with other drugs were similarly disappointing
Conclusion: until a few years ago acute systemic local anesthetic toxicity needed a fresh idea
Adsan, Anesth Analg, 1998

27. A FRESH IDEA Lipid Emulsions expand the list of options
A Decade of research and a growing body of evidence and case reports
The Rescue Kit
Lipid Emulsions expand the list of possible treatments for LA toxicity. Prior to LE there was a lack of clarity when facing LA toxicity in patients. Case reports of “good” outcomes with emergent CPB and a host of different drugs often explained that rapid action in the face of LA toxicity was essential but the best course of action was far from clear.
In 1997 a few researchers began further investigation of a chance experimental finding that Lipid infusions increased the dose of Bupivacaine needed to produce asystole in rats.
There is a growing body of evidence that this may be the best option currently available for the management of LA toxicity.
The advent of the “rescue kit” which includes a 20% lipid emulsion solution has become a standard at many Hospitals that do regional anesthesia.
Weinberg, LipidRescue.com, 2008

28. First To Benefit from Lipid Emulsion
Promising experiments with LA toxicity and Lipid Emulsion resuscitation
Success leads to expanded research
Many of the early studies into lipid emulsions for LA toxicity came from Dr Guy Weinberg at the U of I. One of the earliest studies focused on rats. Two protocols were employed in this study. The protocol I rats received IV pretreatment with either saline or a Lipid Emulsion in a 10%, 20%, or 30% preparation. The median dose required to produce asystole was determined. It was observed that the dose to produce asystole was almost 5 times greater in the 30% LE group than in the saline group. Protocol II focused on a resuscitation model with lipid infused after large doses of LA with similar promising results.
Weinberg speculated that a lipid sink effect was the primary mechanism in the improved outcomes with Lipid Emulsion.
Weinberg, Anesthesiology, 1998

29. Lipid Sink Hypothesis Lipid infusion Lipid phase
Highly lipophilic amino amides
Decreased unbound fraction
The Lipid sink hypothesis states that infusing lipids into the bloodstream creates a lipid phase in the intravascular space. This lipid phase is capable of partitioning a portion of the intrinsically lipophilic local anesthetic molecules reducing the bupivacaine aqueous plasma concentration. With lipid emulsion acting as a “lipid sink” the unbound fraction of LA in plasma available to cause toxicity is decreased.
Weinberg, Anesthesiology, 1998

30. Studies with Lipid Emulsions in a Dog Model
Group
Treatment
MAP mmHg HR
PaO2
PaCO2 pH
Saline
Baseline
/-12
122 +/-17
236 +/-69
36 +/-2
7.38 +/-.04
Recovery
/-3
ASYS
Lipid
/-14
128 +/-21
228 +/- 63
35 +/-2
7.39 +/-.02
/-12
126 +/- 18
212 +/-56
/-2
7.35 +/- .04
This graphic is derived from Lipid Emulsion research in a dog model done in The study involved administration of 10mg/kg Bupivacaine over 10 seconds followed by 10 mins of internal cardiac massage after arrest. Then the 12 dogs divided into two equal treatment groups were given equal volume infusions of either saline or Lipid Emulsion.
As for the saline recovery group….there wasn’t one but all 6 LE dogs recovered.
Weinberg et al, Lipid emulsion infusion rescues dogs, 2003

31. First Lipid Emulsion Resuscitation after Bupivacaine toxicity/arrest
20 min of advanced cardiac life support, a total of 3 mg epinephrine, given in divided doses, 2 mg atropine, 300 mg amiodarone, and 40 U arginine vasopressin were administered. In addition, monophasic defibrillation was used at escalating energy levels-200, 300, 360, and 360 J, according to the advanced cardiac life support protocol. Cardiac rhythms included ventricular tachycardia with a pulse, pulseless ventricular tachycardia that momentarily became ventricular fibrillation, and eventually asystole. The arrhythmias observed during most of the resuscitation period were pulseless ventricular tachycardia and asystole.
The patient was eventually treated with 100 ml of 20% Intralipid given through the peripheral IV. Cardiac compressions continued, and a single defibrillation shock at 360 J was given after the LE. Within seconds, a single sinus beat appeared on the electrocardiogram, and 1 mg atropine and 1 mg epinephrine were administered. Within 15 secs, while external chest compressions were continued, the cardiac rhythm returned to sinus at a rate of 90 beats/min.
Rosenblatt, Anesthesiology, 2006

32. Further Case Studies on LE
LipidRescue lists several case reports of successful resuscitation with LE after CVS toxicity with life threatening rhythms or asystole.
Inferior to randomized double-blinded trials but such investigations would clearly be unethical
Not many case studies giving an account of an unsuccessful resuscitation effort with or without LE although we know such events have occurred
The common case reports usually sound like this:
First, there is injection of large volume of amide local with seizure/LOC/apnea within sec – few mins and airway/breathing intervention undertaken.
Second, a few mins of deteriorating CV function with tachycardia turning to bradycardia or tachyarrhythmia followed by cardiac arrest.
Third, min period during which standard ACLS is employed with a lack of improvement in cardiac function that persists despite multiple attempts at defibrillation and reasonable use of ACLS drugs.
Fourth, at some point a LE bolus is given followed by an infusion.
Next, the same measures within the ACLS algorithm are resumed with a different/better result leading to wide complex tachycardia often within about 5 mins of bolus and eventually return of near normal cardiac function often with negative cardiac enzyme studies post-resuscitation.
Weinberg points out that there is no comprehensive database for all outcomes and he explains that “the literature is very sensitive to bias”. He challenged me to find a case report of a LA related fatality in the past 20 years. So far, I am only aware of one.
Weinberg, Correspondence, 2008

33. Applications of Intralipid in ED
Intralipid has been used to treat other types of drug overdose
Case studies are on the Lipidrerscue.org website.
Same lipid sink idea
In case reports found on the lipidrescue.org website, Intralipid has been shown to effectively treat other overdoses of lipid soluble drugs including tricyclic antidepressants, cocaine, verapamil, propranolol, diltiazem, and a number of others.

34. The Big Question Lipid Emulsions are NO SUBSTITUTE for ACLS.
Where do we insert lipid emulsion administration into the ACLS algorithm?
How is the drug given?
Lipid emulsions are no substitute for ACLS. Without airway and breathing no LE is going to save the day so rather than jumping straight to the use of lipids follow the established pathway. This is best for the patient clinically and wiser for the practitioner.
Dr Weinberg was asked where he recommends inserting Lipid Emulsion Bolus into an ACLS response for resuscitation in acute systemic toxicity. His response: “this is the (big) question. Originally, we said, ‘last resort’ since there was little evidence of clinical efficacy. Now there is unquestionably a trend to start sooner, hoping to prevent progression to arrest.
Dosing 1.5 mL/kg as an initial bolus, followed by an infusion of 0.25 mL/kg/min for minutes. Bolus could be repeated 1-2 times for persistent asystole Infusion rate could be increased if the BP declines.
Weinberg, correspondence, 2008

35. primum non nocere Risks of Lipid Emulsion Infusion: all < 1%
Modulation of cytokine production by WBCs
Altered inflammatory response
Weakness, altered MS, seizures in children
Fat emboli if lipid particles >5 microns in diameter
Hyperlipedemia
Pulmonary hypertension
anaphylaxis especially if prepared from soybean oil (most likely adverse reaction with acute, short-term administration)
\ˌprē-mu̇m-ˌnōn-nȯ-ˈkāy-rāy\ ‘First do no harm’ is important.
So what harm can come from a lipid emulsion bolus?
This is a list of most common adverse reactions to Lipid Emulsion Infusion although a bolus of LE may present some unique unknown risks.
All of these adverse reactions listed by the manufacturer occur <1% of the time
Of course, nothing on this list sounds worse than cardiac arrest
The most recent case reports found on the LipidRescue website are cases of earlier administration of LE. The outcomes of the case reports published seem better than the older reports where LE was given after 30 mins or more. Duration of CPR was shorter and in one case resumption of NSR occurred before they could get the defibrillator to the bedside after IntraLipid was given immediately following evidence of an intravascular injection.

36. References
Arthur GR: Alterations in the pharmacokinetic properties of amide local anesthetics following local anesthetic induced convulsions. Acta Anaesthesiol Scand 32:522, 1988
Barash P: Clinical Anesthesia, 5th edition, chapter 17, 2006
Clarkson C: Mechanism for bupivacaine depression of cardiac conduction: fast block of sodium channels
during the action potential with slow recovery from block during diastole. Anesthesiology 1985;62:
Colin J: Intravenous ropivacaine bolus is a reliable marker of intravascular injection in premedicated healthy
Volunteers. Canadian Journal of Anesthesia50: 8 / pp 795–800, 2003
Cotileas P: Bupivacaine-Induced Myocardial Depression and Pulmonary Edema: A Case Report. Journal of Electrocardiology Vol. 33 No
Katzung B: Basic & Clinical Pharmacology, 10th Edition, Chapter 26
Kim J: Continuous mixed venous oxygen saturation, not mean blood pressure, is associated with early bupivacaine cardiotoxicity in dogs. Canadian Journal of Anesthesia 50: (2003)
Mather L: Acute Toxicity of LA: Underlying Pharmacokinetic and Pharmacodynamic Concepts, Regional Anesthesia and Pain Medicine, Vol 30, No. 6, 2005
Miller R: Miller’s Anesthesia, 6th Edition, Chapter 14, 2005
Mischa J: The effects of Age on Neural Blockade and Hemodynamic Changes After Epidural Anesthesia with Ropivacaine. International Anesthesia Research Society, 94(5): , 2002
Morgan and Mikhail, 4th edition, Chapter 14, 2006
Rosenberg H: maximum Recommended Doses of Local Anesthetics: A multifactorial Concept. American Society of Regional Anesthesia and Pain Medicine, 29 (6): , 2004
ScottD: EDITORIAL: “Maximum Recommended Doses” of Local Anesthetic Drugs. British Journal of Anesthesia Vol 63, No. 4, 1989.
Shigeo O: Systemic Toxicity and Resuscitation in Bupivacaine, Levobupivacaine, or Ropivacaine Infused Rats. Anesth Analg 2001;93:743–8)
Weinberg G: Lipid emulsion infusion rescues dogs from Bupivacaine induced cardiac toxicity. Regional Anesthesia and Pain Medicine, Vol 28, No 3 : , 2003
Weinberg G: Pretreatment or Resuscitation with a Lipid Infusion Shifts the Dose-Response to Bupivacaine-induced Asystole in Rats. Anesthesiology:Volume 88(4)April 1998pp
Warren J: Reversal of Central Nervous System and Cardiac Toxicity After Local Anesthetic Intoxication by Lipid Emulsion Injection. International Anesthesia Research Society, Volume 106(5): , 2008
Yokoyama M: Effect of Vasoconstrictive Agents added to lidocaine on IV lidocaine-induced convulsions in rats. Anesthesiology 82:574,1995
In conclusion whenever large volumes of bupivicaine, ropivicaine or other lipid soluble local anesthetics are being injected for regional blocks the risk of intravascular injection and life threatening cardiovascular toxicity is there and so in my practice, a 20% lipid emulsion like intralipid is also there along with the rest of the equipment used to do the block to ensure that if a rare intravascular injection occurs the patient can be rapidly and effectively treated. Case reports indicate that early treatment with LE like IntraLipid tends to result in better outcomes when life threatening local anesthetic toxicity occurs.

37. This slide speaks for itself