Past, Present, and Future of Lipid Resuscitation Therapy

Abstract

Lipid resuscitation therapy was identified in 1998 as an effective treatment for local anesthetic systemic toxicity in an animal model. Since the original observation, the field has progressed tremendously with successful clinical translation and expansion of use to treatment of other types of drug overdose. Recent work has expanded our understanding of the mechanism of this novel treatment, one that includes both a dynamic scavenging component and direct cardiotonic effect. In this review, we discuss the past, present, and future of lipid resuscitation therapy with a focus on our understanding of the mechanism and directions that the field is moving, both from a clinical and basic research side.
© 2015 American Society for Parenteral and Enteral Nutrition.

Full text

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Past, Present & Future of Lipid Resuscitation Therapy
Authors: Michael R Fettiplace MS*,1,2,3, Guy Weinberg, MD1,2,
Affiliations: 1: Department of Anesthesiology, University of Illinois College of Medicine,
Chicago, Illinois 2: Research & Development Service, Jesse Brown Veterans Affairs
Medical Center 3: Neuroscience Program, University of Illinois at Chicago, Chicago,
Illinois, USA
Funding: Dr Weinberg is supported by a United States Veterans Administration
(Washington DC, USA) Merit Review and a NIH CounterACT grant 1U01NS083457-01.
Mr Fettiplace is supported by the Department of Anesthesiology, University of Illinois
College of Medicine (Chicago, IL, USA), an American Heart Association (Dallas, TX,
USA) Pre-doctoral Fellowship 13PRE16810063 (Fettiplace).
Key Words: Intralipid, Lipid Emulsion, Bupivacaine, toxicity, overdose, local anesthetic,
Word (including references): 10561
Corresponding Author:
Michael Fettiplace,
Department of Anesthesiology M/C515
University of Illinois Hospital & Health Sciences System
1740 W. Taylor
Chicago, IL 60612
Fax: 312-569-8114
Email: mfetti3@uic.edu
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Conflict of Interest: Dr. Weinberg was awarded United States patent 7,261,903 B1
“Lipid Emulsion in the Treatment of Systemic Poisoning” and is a co-founder of ResQ
Pharma, an LLC seeking improved methods of resuscitation. Dr. Weinberg also created
and maintains www.lipidrescue.org, an educational web site on the use of lipid emulsion
in treating drug toxicity

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Abstract
Lipid resuscitation therapy was identified in 1998 as an effective treatment for local
anesthetic systemic toxicity in an animal model. Since the original observation, the field
has progressed tremendously with successful clinical translation and expansion of use
to treatment of other types of drug overdose. Recent work has expanded our
understanding of the mechanism of this novel treatment, one that includes both a
dynamic scavenging component and direct cardiotonic effect. In this review we discuss
the past, present and future of lipid resuscitation therapy with a focus on our
understanding of the mechanism and directions that the field is moving both from a
clinical and basic research side.
Clinical Relevancy
Drug overdose from both illicit and prescription drugs is a serious health problem and
cause of mortality in the United States. Lipid resuscitation therapy (LRT) is used
clinically as an antidote for local anesthetic systemic toxicity and non-specific xenobiotic
overdose. This review provides a history of the field; summarizes our understanding of
the mechanism of LRT; evaluates the evidence about what drugs are amenable to
treatment with LRT; and discusses possible methods to improve LRT.
PART I. Introduction & Overview
Very soon after the commercial release of Intralipid® in 1962, scientists and clinicians
started to propose the use of intravenous oil and fat emulsions as drug binders or as

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components of extracorporeal lipid dialysis. In that same year, Russell and Westfall
reported that intravenous corn and cottonseed oil could shorten the duration of
thiopental anesthesia1. Subsequent to this, in 1965, Shinaberger and colleagues
demonstrated that adding olive or cottonseed oil to the dialysate could enhance removal
of glutethimide2, with a report of successful use of lipid extracorporeal hemodialysis on
a patient a few years later3. In the following years, specialized devices for lipid dialysis
were developed4 and proposals of more specially designed dialytes for detoxification
were postulated5. Laboratory investigations demonstrated that the addition of corn oil to
dialytes was effective at moving drug out of the plasma and into the dialyte, particularly
for imipramine, amitriptyline, methaqualone and glutethimide6. Further, in 1974
Krigelstein and colleagues were the first to demonstrate that a commercially-available
fat emulsion (10% Lipofundin, B. Braun, Taguig City, Philippines) could bind
chlorpromazine in vitro and save rats from lethal chlorpromazine toxicity in vivo.7 The
field soon went quiet and the clinical translation of lipid dialysis was not pursued as
interest of the community moved to pharmacological interventions for overdose. Then,
in 1998 it was demonstrated that pretreating or resuscitating rats with an intravenous
infusion of lipid emulsion (ILE, 20% Intralipid®, Baxter Pharmaceuticals, Deerfield, IL)
without accompanying dialysis could increase the median lethal dose of intravenous
bupivacaine8. This initial finding was promising because bupivacaine toxicity can
produce an intractable cardiac arrest that was viewed for many year as potentially un-
treatable.9 These findings were confirmed for a dog model in 2003 with the evidence
that after ten minutes of bupivacaine-induced hypotension, all dogs given ILE recovered
normal vital signs while all saline-treated controls died.10 Findings in both of these

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models were experimentally interesting, but they did not constitute a clinical
breakthrough.
The first clinical translation of lipid resuscitation therapy (LRT) was reported in two
separate cases of local anesthetic systemic toxicity (LAST) in 2006 by Meg Rosenblatt11
and Rainer Litz12. Rosenblatt et al described a patient treated with 20mL bupivacaine
and 20mL of mepivacaine for regional anesthesia of the brachial plexus. The patient
progressed to seizures and asystole. When the patient did not respond to traditional
advanced-cardiac-life support, 100mL of 20% Intralipid® was injected and within
seconds a cardiac rhythm resumed. In a similar scenario in the case of Litz et al, a
woman received 40mL of 1% ropivacaine that was followed by seizures and asystole.
When epinephrine failed to revive the patient, 100mL of Intralipid® was administered by
bolus with another 100mL delivered over the subsequent 10 minutes at 10 mL/min
leading to rapid hemodynamic recovery from toxicity. Following these reports, many
more cases were reported with examples of successful resuscitation from overdoses of
bupivacaine11,13–25, mepivacaine26,27, ropivacaine12,28–30, and lidocaine15,30,31. Taken
together, these observations indicated the successful clinical translation of the original
laboratory finding. Within the anesthesia community, the result rapidly changed practice
for treatment of LAST with ILE replacing vasopressors as the first therapy for suspected
LAST and fueling recommendations to incorporate lipid infusion from professional
organizations.32–35
Standard Dosing: In the case of a suspected local anesthetic overdose, the standard
recommendation from these professional organization for LRT is a dose of 1.5mL/kg

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lean body mass (~100mL for an adult) of 20% lipid emulsion delivered as a bolus over 1
minute followed by a continuous infusion of 0.25 mL/kg/min for a least 10 minutes after
return of spontaneous circulation. The bolus could be repeated once or the infusion
doubled for continued hypotension but the total dose including both bolus and infusion
should not exceed 12mL/kg (~800-1000mL for an adult).32–35 This keeps the total dose
of lipid below the 24-hour limit of 12.5mL/kg of 20% lipid emulsion set by the FDA.
Local anesthetic systemic toxicity: Following the clinical translation, lipid
resuscitation therapy has provided an effective treatment option for LAST. However,
like many famous treatments including penicillin & aspirin, the mechanism was not
understood at the time of discovery or clinical translation. Even more vexing, we do not
fully understand the key mechanisms underlying LAST itself. Like many medicines,
local anesthetics are small, amphipathic molecules that at low concentrations exert
specific effects but as concentrations increase they can bind to unintended targets
inside the cell and disrupt normal cellular and physiologic homeostasis. Local
anesthestics are used clinically to inhibit pain transmission by blocking voltage gated
sodium channels. However, orders of magnitude below their sodium channel blocking
threshold36,37, they can interfere with intracellular signaling38 and above their sodium
channel blocking threshold they interfere with mitochondrial metabolism, thereby
altering oxidative phosphorylation39. These multiple effects lead to a combination of
systematic issues with both vasodilation40 and cardiac collapse41. It is still unclear
which effect is responsible for the lethality of LAST9. The problem is complex and

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incompletely understood and the mechanism of LAST most likely underlies its
responsiveness to treatment with LRT.
PART II: Mechanism of lipid emulsion therapy
Intertwined into the history of LRT is the progression of ideas about how LRT works to
reverse local anesthetic toxicity. The original mechanistic hypothesis proposed by
Weinberg and colleagues in 1998 was that the lipid emulsion could provide a novel
compartment for drug to partition into once injected intravenously8. This idea became
known colloquially as “the lipid sink”. The theory of a partitioning effect comported with
early studies of lipid dialysis as a rescue agent1–5. Further, studies by Mazoit and
colleagues42 also agreed with earlier in vitro binding studies6,7, demonstrating that lipid
emulsion would capture drugs based on the drugs octanol:water coefficient (LogP).
However, more recent studies have elucidated that the full rescue effect of LRT during
LAST is multi-modal. The mechanism of LRT-based reversal includes both a
scavenging effect that removes drug from tissue and a direct-cardiac effect that
improves cardiac output once drug is removed from cardiac tissue.43 Of note, the
cardiotonic effect only occurs once drug concentrations in cardiac tissue drops below
ion-channel blocking thresholds.
Scavenging effects
First, the ILE used during LRT provides a compartment for drugs to partition into as
confirmed by in vitro42,44,45, ex vivo46,47, and in vivo studies43. In vitro studies have also
demonstrated that lipid emulsion can accelerate the recovery of channel conductance

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and facilitate the return of protein signaling systems when delivered to cell and tissue
preparations undergoing toxicity48–53. This is true for sodium channels48,49,53 and
phenylephrine dependent vasoconstriction50–52. Based on the in vivo studies, the
intravenous lipid compartments do not permanently sequester the drug, but instead
accelerates redistribution of drug. Thus, LRT can facilitate recovery while not directly
contributing an obvious “sink”.54 For local-anesthetics like bupivacaine, this accelerates
the movement of drug from drug-susceptible organs, like the brain and heart, to organs
that can store (muscle, adipose), detoxify (liver), and excrete (kidney, bladder) the
drug.43,55 This mechanism of improved redistribution by ILE has also been observed in
human models for local anesthetics56,57 and amitriptyline.58 In both of these cases, the
lipid transiently captures drug in the lipid-laden plasma and rapidly moves it to other
organs.
Therefore, with our improved understanding of lipid resuscitation, we view lipid as
more of a “shuttle” to move drug around as opposed to a “sink” which contains a pure
capture mechanic. Litonius and colleagues discussed this effect in a human-model as a
“shortening of the context-sensitive half-life”56 while Kazemi and colleagues termed this
as a hypothetical subway instead of sink59. This “lipid shuttle” or capture/release
mechanism has significant implications on what drugs and situations that lipid can be
useful for. Additionally, in the case of recovery from toxicity, this accelerated
redistribution is a very powerful mechanic, but also illustrates the need for continued
cardiopulmonary resuscitation efforts including chest compressions and ventilation.
Non-scavenging or direct-cardiac effects

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Direct benefits of the lipid on cardiac output, independent of the scavenging effects,
have been seen in a number of systems. Scavenging effects on their own cannot
explain the rapid recovery from LAST60 but the addition of a direct cardiac effect can
explain this rapid recovery43,61. These non-scavenging effects improve cardiac output
both in the absence of toxicity62,63 and during toxicity43 confirming the suspicion that lipid
emulsions like Intralipid® can provide direct physiological effects on the heart or
vasculature64. In vitro comparisons of the effect of LRT on different local-anesthetics
has also demonstrated the presence of direct effects on a cellular level. Despite the
issue that the LogP of mepivacaine makes it less susceptible to scavenging by binding,
studies by Wagner et al demonstrated that lipid has a direct effect on cardiomyocytes in
vitro that were also exposed to mepivacaine.48 The improved cardiac output improves
the blood pressure, which is often a concern with local anesthetic toxicity. In addition it
continues to facilitate the accelerated redistribution.
The underlying cause of improved cardiac output via lipid emulsion is unclear but
remains an interesting basic science question. The volume of ILE is a definite
component but the other contributors are unclear.61 Many ideas have been proposed,
most of which lack convincing scientific evidence or have too many experimental
confounders. The two most popular hypotheses are “the calcium hypothesis” and “fatty
acid hypothesis.” Gueret proposed the calcium hypothesis in an editorial, claiming that
fatty-acids increase Ca+ influx into cardiac myocytes to produce inotropy65. He cited a
single article from 1992 in support of the idea that used guinea pig ventricles66. Many
others have repeated this calcium hypothesis without providing experimental data.
However, many subsequent studies (some from the same group that performed the

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1992 study) have demonstrated that fatty-acids inhibit calcium influx in more suitable
animal models67–72. Therefore, based on the experimental literature, this hypothesis is
unlikely. A second hypothesis is an assertion that the mass action of lipid emulsion can
overcome the block in fatty-acid processing that bupivacaine causes.39 This hypothesis
is also unlikely because cardiac output does not recover until drug concentrations in the
myocardium drop below the thresholds for blockade of mitochondrial function.43 Other
ideas have been proposed but many have significant methodological issue related to
the local-anesthetic insult. Inhibitor studies are problematic because the lipid can
sequester the inhibitor-compound in addition to the drug of interest (most often
bupivacaine). Additionally, local anesthetics including bupivacaine, lidocaine39 and
cocaine73 block fatty-acid processing in the mitochondria which produces an ischemic-
like injury. Thus, the combinatorial toxicity of other agents (especially agents which
exacerbate ischemic injury) with bupivacaine makes results uninterpretable without
appropriate controls. A few studies have pointed to fatty acid processing and
compounds used in ischemia-reperfusion injury as inhibiting the direct-effects of lipid,
but most failed to account for the potential combinatorial effects with bupivacaine. As
such, their contribution to mechanism of LRT is very hard to infer. Finally, there is
evidence that the vasoconstrictive properties of Intralipid® in the vasculature plays a
role, but the relative contributions of cardiac versus vascular aspects is unclear.74
Future mechanistic directions
There are a number of questions left to answer about the mechanism both in regard to
the scavenging component and in regard to the direct effects. It is not entirely clear

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whether LogP is the only predictor of the scavenging effect. As with other drugs,
partitioning can occur due to a combination of lipophilicity (LogP) and pH75,76. As such,
there may be other factors that contribute to partitioning by Intralipid® that could explain
how Intralipid® effectively treats overdoses from less-lipophilic drugs77–79. Additionally,
the characteristics and evolution of the intravenous scavenging effect of Intralipid® is
incompletely described. A better understanding of it could help aid optimal dosing or
inform on next generation therapies. In regard to the direct cardiac effects, there is still
a lot to understand. The primary theories of calcium influx and mass action have little
evidence to support them. Alternative theories have been proposed that involve the
vasculature74, channel specific effects48, fatty-acid processing80, intracellular signaling81
and mitochondria41,82. One or more of these systems is likely involved but the exact
mechanisms are still a matter of speculation.
PART III. Clinical future
While local anesthetics provide a good model to investigate the mechanism of LRT, the
larger clinical future use of LRT as a treatment lies outside of the realm of local
anesthetics. Clinically significant LAST occurs at a rate of roughly 1:1000 nerve blocks
and while precise numbers aren’t available, cardiovascular collapse with LAST is an
infrequent event. This rate will hopefully decline as improved awareness and
methodologies like ultrasound guidance are adopted.83,84 Prescription drug overdoses
are still a major cause of death in United States, outpacing car accidents, suicide and
sepsis in the past ten years85–87. Therefore, it was an important step when Dr. Archie
Sirriani saved a patient from a buprorpion and lamotrigine overdose using LRT in

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2008,88 opening the door to use of LRT as antidote to an important public health
problem.
Even with this transition to a more general antidote, the clinical future of ILE is
still undefined. Recommendations from professional societies are modified versions of
local anesthetic recommendations35 even though the pharmacokinetic of non-local
anesthetic overdoses are clearly very different from those in local anesthetic overdose.
In particular, local anesthetic overdoses are parenteral in nature with direct injection of
drug into the vasculature or relatively rapid absorption from a tissue depot. In contrast,
non-local anesthetic overdoses are most often enteral in nature due to either intentional
or accidental ingestion of a prescription medication. These differences will necessitate
different treatment strategies, which are currently being defined.73
Without a broader base of clinical research to draw on, insight into the usefulness
of lipid for different toxicities comes to us either from basic science studies or clinical
case reports. A number of articles have compiled and evaluated the use of lipid in
human clinical situations, all coming to similar conclusions89–92. For both local anesthetic
and non-local anesthetic overdoses, only low-level evidence, comprising largely animal
models and case reports, exists in support of using LRT. Beyond case reports, a
clinical registry demonstrated an improvement in Glasgow-coma scale (GCS) and blood
pressure associated with use of ILE93. A randomized clinical trial from Iran of treatment
of non-local anesthetic overdose found the same effect of improvement in GCS in
patients treated with lipid relative to those untreated.94 All these retrospective analyses
have come to the conclusion that the evidence is strongest for the treatment of LAST
but evidence for treating toxicity aside from LAST is less compelling. Recently a

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working group was formed by the American Academy of Clinical Toxicologists with the
explicit purpose of providing guidelines for the use of LRT in both local anesthetic and
overdose from other drugs based on the available evidence.95 While it is obvious that
robust clinical trials are needed for non-local anesthetic toxicity (with appropriate dosing
and timing), in the interim lipid will remain as a ‘Lazarus’ measure for many overdoses.
In the following section we will address the evidence for efficacy of LRT beyond treating
local anesthetics and the questions that need to be answered to move LRT forward as a
general antidote.
Cocaine
As one of the most widely used recreational drugs, cocaine overdose is a problem that
has not been adequately addressed insofar as there are no specific antidotes and
treatment is largely suppoprtive96. Cocaine is a potent local-anesthetic and therefore it
is reasonable to infer that it might be amenable to ILE treatment given that it has similar
physicochemical properties as other local anesthetics and that its toxicity is based on
similar mechanisms of action. Two case reports describe the successful treatment of
cocaine toxicity with ILE97,98 and two basic science studies demonstrate the
effectiveness of ILE in animal models of cocaine overdose99,100. Further, lipid also
reverses the cardiac depression caused by the both cocaine and cocaethylene, a
byproduct of co-administration of ethanol and cocaine100. As cocaine is primarily
ingested parenterally, either by smoking or absorption through mucus membranes, the
parenteral nature of the overdose makes it’s treatment with LRT more similar to that for
LAST.

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Other Illicit Drugs
Heroin and opiates cause the most drug-related deaths in the United States, but as
there exists a specific, highly effective receptor antagonist there is very little relevance
of lipid to these overdoses.101 Two categories of illicit drugs that might benefit from lipid
infusion are the synthetic cathinones commonly referred to as “bath salts”, and both
synthetic and natural cannabinoids102, both of which are lipophilic. Of the cathinones,
alpha-pyrrolidinopenthiophenone has a LogP of 3.65 and 3,4-
methylenedioxypyrovalerone has a LogP of 3.06. Of the cannabinoids,
tetrahydrocannabinol has a LogP of 7.68. Further, lipid has already been used to treat
marijuana intoxication in dogs103.
Anti-anxiety & sleep aids
Gaba-ergic medications that function as anti-anxiety or sleep aids are the most-
prominent cause of drug-related emergency room visits. These are often treated with
with supportive care. Additionally, the gabaergic antagonist, flumazenil, is reported to
aid in treatment of these overdoses, but is used infrequently104 potentially due to
concerns about seizures or other complications105. A very limited number of case
reports have described treatment of overdoses in this group with LRT including
clonazepam106, diazepam107 and zolpidem/alprazolam108. However, all of these reports
were presentations of multi-drug overdose. No animal models exist for benzodiazepine
overdose treated with LRT and coupled with the lack of case reports, it is impossible to
assess potential effectiveness of Intralipid® for anti-anxiety agents. However, since

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they comprise such a significant cause of drug-related ED admissions, lipid or
liposomes for benzodiazepine toxicity should be studied more. As an over-the-counter
sleep aid and motion sickness medication, diphenhydramine also poses the risk of
overdose. A few recent reports have identified that lipid is apparently beneficial in
diphenhydramine overdose.109–111
Antidepressants & Antipsychotics
The first case of non-local anesthetic toxicity which was treated with lipid was a case of
combined lamotrigine and bupropion overdose.88 Many anti-psychotic or antidepressant
medications make sense as treatment targets with ILE because of the lipophilicity
needed to cross the blood-brain-barrier and because of their structural similarity with
local anesthetics. Since the first case report, a significant number of other toxicities
have been treated with LRT including amitriptyline111–117, quetiapine106,114,
lamotrigine78,79,88,114, bupropion88,118–120, and doxepin121. Rabbit models have
demonstrated the effectiveness of lipid as a treatment for intravenous clomimpramine
toxicity122–124. Further, in pig studies lipid is shown to entrap amitriptyline into the
plasma58, comporting with the scavenging theory.
However, there have also been negative results. A number of pig studies have
demonstrated no beneficial effect of ILE on amitriptyline overdose125,126, but
interpretation of these results is problematic because pigs suffer from a systemic
hypersensitivity reaction to Intralipid® leading to pulmonary hypertension and arterial
oxygen desaturation.127–130 In a similar study in rats with oral amitriptyline overdose, ILE

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reduced survival compared to other groups.131 We will discuss the question of oral
overdoses in “Part IV: Next-Generation Lipid Therapy”.
Antidepressants and antipsychotics were among the drugs treated in the registry
study93 and a preliminary clinical trial of lipid in in non-local anesthetic overdose.94
Based on the positive results in case reports, animal models, clinical reviews, and
registry reports, it seems that both antidepressants and antipsychotics hold potential as
targets for scavenging therapy. Additional work should be promoted to better
understand dosing and to identify specific scenarios where lipid may provide benefit.
Cardiac medications
Another group of drugs that pose a risk of overdose, particularly in elderly populations
are cardiac medications especially beta-blockers and calcium-channel-blockers.
Overdoses with β-blockers, propranalol108,132–134 and metoprolol107,114,135,136 have been
treated with LRT. However, animal studies have not demonstrated similarly promising
results. These studies demonstrate that Intralipid® may be beneficial in more lipophilic
beta-blocker toxicity, providing benefit for propranolol-induced hypotension in rabbits137
and rats138, and some benefit in atenolol toxicity139 but no benefit to blood pressure in
metoprolol toxicity140. Further, in the case of propranolol-induced hypotension,
Intralipid® was not as effective as insulin/glucose for ameliorating toxicity in rabbits141.
Mechanistically we know that adrenergic signaling can interfere with LRT142 and it is
possible that beta-blockers as well as adrenergic-agonists will produce some
interference with the positive effects of ILE as adrenergic sensitization is one of the
theories of lipid-induced vasoconstriction.143

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In contrast, the results for treatment of calcium-channel blocker toxicity have
been more promising. Many case reports have asserted the usefulness of LRT for
calcium channel blocker overdose including verapamil90,93,144–149 diltiazem93,150–153 and
amlodipine136,149,154–156 overdose. Further, in experimental settings ILE has benefitted
animals with intravenous verapamil toxicity157–159. However, in a rat model of oral
overdose, supplementation of lipid made toxicity worse, potentially by pulling drug into
the vascular space131. How optimal treatment of oral overdoses might differ from that
for parenteral (read, local anesthetic or cocaine) overdose is a clinically relevant and
complex issue.
Veterinary Overdoses
Outside of human medicine, LRT has provided significant benefit for poisoned animals.
A number of other reviews have covered the use of ILE in veterinary medicine.160–162 In
particular, Intralipid® has been used extensively to treat Ivermectin77,163–166 and
Permethrin167–170 toxicity. In particular, Peacock et al conducted a randomized trial of
lipid emulsion in permethrin toxicosis in felines and found a robust rescue effect of the
lipid emulsion in comparison to saline.171 Beyond that a number of other overdoses with
potential translational relevance have been reported as effectively managed with ILE
including Moxidectin172, Ibuprofen173, Carbamazepine106,119, and Baclofen106. Baclofen
is interesting in particular because it is non-lipophilic and may serve as a good model of
how lipid can be used to treat non-lipophilic drug overdose. Finally, ILE has been used
to treat marijuana intoxication in dogs103. This is also of interest because of the

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increase in marijuana overdose following its legalization for medical and recreational
purposes.102
Herbicide overdose
The weed-killer glyphosate has the potential for serious complications in humans
following intentional or accidental exposure and LRT has been reported to alleviate
toxicity in patients.174 The possibility that Intralipid® could provide benefit for herbicide
toxicity like glyphosate certainly warrants further study.175
Clinical Trial
Beyond a greater understanding of the mechanism, the greatest challenge in LRT is
designing a clinical trial to test the clinical efficacy compared to other standard
treatments. Currently, the treatment algorithm for drug overdose is a grab-bag of
medications including multiple-pressors, sodium bicarbonate, high dose insulin,
methylene blue and LRT, the latter often only given when all other options are
exhausted. In the case of calcium-channel-blocker overdose, none of these treatment
options has evidence beyond low-level animal models and case reports to support the
usage176. Even high dose insulin lacks clinical trials to support its use. As such, the
majority of antidotes for drug overdose are assessed by animal studies, case reports,
physician experience/preference and expert opinion. In the case of local anesthetics,
we know that high-dose epinephrine can interfere with the effectiveness of ILE177 and
that vasopressors are less effective at treating overdose in animal models.178. As such,
treatment algorithms for LAST recommend the use of LRT before vasopressors.

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However, the same is not known for other drugs and extrapolating from animal models
of LAST is questionable. Before progressing to trials, a better understanding of dosing
and timing for LRT in oral overdose is needed, along with a better understanding of
which specific drugs might be amenable to treatment. Of possible drug candidates, we
support continued investigation of drugs with greater basic-science and case study
validation, including calcium-channel blockers, bupropion, tricyclic antidepressants and
cocaine.
PART IV. Next generation lipid therapy
As we move to a better understanding of the mechanisms of LRT and parse out the
separate effects contributed by the scavenging and the direct cardiotonic mechanisms
(as well as other possible effects) we can begin to design next-generation agents for the
treatment of drug toxicity. The following section discusses some of the questions in the
future of LRT.
Optimizing treatment for Oral overdoses
The pharmacokinetics of oral overdose are fundamentally different from those of
intravenous or parenteral toxicity and therefore require a different dosing of LRT. Oral
overdose will lead to prolonged adsorption of drug from the gastrointestinal tract. A
number of animal models have demonstrated that lipid could be less effective in treating
oral overdose131. Cave, Harvey and Graudins raised the possibility that early treatment
with lipid in oral overdoses could accelerate toxicity179. As the mechanism of lipid is
partially driven by redistribution, this effect could theoretically increase the rate of

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absorption of a lipophilic drug from the GI tract and movement to sites of toxicity before
movement to sites for storage and detoxification. Since oral overdose remains a
significant issue, there is a pressing need to understand how ILE will modify the
pharmacokinetics and drug parameters of an oral overdose. Further there is a need to
determine how timing and dosing of ILE will change based on type of drug.73
Refinement of dosing/delivery recommendations
As part of the oral overdose question, there is a broader question about optimal dosing.
We know that lipid provides a dose-dependent response with 30% Intralipid®
accelerating the speed of recovery relative to 20% ILE in an animal model of
bupivacaine overdose61. Higher percentage formulations (>40%) break down due to
instability, but a higher dosage like 30% might function as a better clinical antidote than
the current clinical standard of 20%. Further, there are questions about the bolus
volume and the rate of a subsequent infusion. Dosing will differ based on intoxication
route as we have discussed in regard to oral overdoses but there are other
considerations. We need a better understanding of the pharmacokinetics and
pharmacodynamics of drug-induced toxicity and how different infusion paradigms might
modify these pharmacokinetics for a given drug. We might then be able to optimize and
simplify the dosing recommendations. Finally, we know the lipid is effective when
delivered via the intraosseous space and this may change treatment options in high-risk
or battlefield overdose situations, but further research is needed180. As mentioned
earlier, a working group has been developed to provide recommendations for use of
LRT in both local-anesthetic and non-local-anesthetic toxicity.95 Standardization of use

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is a worthy goal for current usage parameters of LRT as a “Lazarus” measure with
bolus+infusion derived tom LAST treatment recommendations. However, current
guidelines outside of LAST are almost certainly non-optimal and may be far from
optimal based on new mechanistic insight.43,73 Better dosing and timing
recommendations are needed. These should be determined in basic models and
ultimately tested in randomized trials for the highest quality of evidence.
Better scavengers
The drug delivery community is interested in developing next-generation drug
scavenging agents181,182 and one expects that reverse engineering of the principles
underlying drug delivery will yield effective and efficient scavengers. Intralipid® was not
originally designed as a drug binding agent and it is likely that other agents with higher
binding capacities and greater specificity could be developed. Some assert that the
major binding capacity in Intralipid® comes from the phospholipids used to emulsify the
soybean oil. If this is the case then increasing the amount of phospholipids could
increase the lipophilic binding capacity and provide a greater drug capturing potential.
Alternatively, different properties like surface charge could be used to more effectively
scavenge charged agents. In particular, pH-gradient liposomes are already studied
experimentally as capture agents183–185 because of their widely studied properties as
drug-delivery agents186,187. Other, next-generation strategies for drug scavenging have
been developed185,188–190 and they hold significant promise for the future and potential
clinical use. Two recent reviews have discussed in more depth the current field of
liposomal scavenging systems and the possibilities they hold.191,192 One major

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advantage of liposomal delivery systems is their ability to hold drug. This property
differentiates them from LRT, which captures & releases drug to facilitate accelerated
redistribution. In some cases, the pure capture may improve recovery relative to
Intralipid® but in other cases, the capture/release mechanism might be preferred.
Liposomes hold much promise, but there are many practical and regulatory hurdles
before they become clinical tools.
Combinatorial therapy
Alternatively, combinatorial binding schemes could be considered in future
detoxification scenarios. Many other binding agents have been proposed for treatment
of toxicity and could be used alone or in combination with ILEs. Cyclodextrins have
been used for reversal of drug toxicity193 or as a binding agent for cocaine194 even
though they are not as effective at reversing cocaine toxicity as Intralipid®.100 Additional
work is needed to refine these agents or combinations.
Since ILE exerts scavenging-independent effects, any advance in LRT must
improve on both the scavenging and non-scavenging components of LRT. As an
example, liposomes have been compared in animal models against traditional ILEs but
do not produce the same level of recovery122. A number of agents are currently used to
provide cardiotonic effects during overdose and could be used to supplement pure
binding agents. High dose insulin is used extensively for calcium-channel-blocker
overdose and the combination of ILE and high dose insulin have been used together
effectively149,152,195. Insulin and lipid co-administration in animal models does not seem
to produce synergistic effects because they may activate overlapping metabolic rescue

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22!
pathways. However, there does not seem to be a contraindication to giving them
concurrently as insulin has shown benefit in some circumstances141, and LRT has been
shown better in others63,196. Another alternative is methylene blue which will increase
the median survival time for calcium-channel blocker toxicity by increasing pulse rate
and mean arterial pressure.197 Other reviews have covered the topic well, with the
conclusion that 1-2mg/kg of 1% methylene blue can be beneficial in toxin-induced shock
as an adjuvant to vasopressors198
Lipid as a dialysis agent
Finally, we return to the beginning. One of the more exciting recent developments is the
suggestion that lipid or optimized liposomes could be used as an intraperitoneal dialysis
agent. Intralipid® was examined as a dialysis agent for an animal model of
clomipramine toxicity54 with the combination of ILE and plasma exchange providing the
greatest benefit. Further, Forester and colleagues have developed a novel liposomal
formulation which may offer more optimized peritoneal capture properties189. The use
of lipid as a hemodialysis or peritoneal dialysis agent could provide benefit in the case
of extended toxicity such as oral overdose of a drug with an extremely long
pharmacokinetic half-life. However, the clinical usefulness of such ideas remains to be
seen with many experimental, clinical and regulatory hurdles to address.
PART V. Conclusion & Future Directions
LRT has progressed significantly since the demonstration of its efficacy in the rat and
dog models of severe, local anesthetic overdose. In the past few years, our

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23!
understanding of the mechanism has evolved substantially with recovery being driven
by a combination of a “lipid shuttle” and a direct cardiotonic effect, both of which
accelerate redistribution of the toxin. Further, the development of next generation
agents is progressing with hope for clinical translation in the near future. For now there
is much work left to do. We still need to assess what drugs are most amenable to
treatment with LRT, determine optimal dosing parameters for oral overdoses and
implement a randomized, controlled clinical study to test and compare effectiveness
with other treatments. The latter is of great need as only low-level evidence exists for
treatment. In the interim, we recommend further research on reversing toxicity of drugs
that pose significant clinical problems and have higher likelihood of success of
treatment by ILE. Examples of these include tricyclics, bupropion, calcium channel
blockers and cocaine. In particular, the method of gaining greatest benefit from LRT in
treating an oral overdose needs to be addressed. As part of this question, optimal
dosing & timing need to be determined since the current treatment paradigm used in
parenteral overdoses could likely be modified with improved results specifically for oral
intoxications. The field is full of exciting questions to answer and progress will lead to
lives saved since drug toxicity remains a significant problem worldwide.

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24!
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