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Emergency Medicine News:
doi: 10.1097/01.EEM.0000365491.78256.84
Infocus

Novel Antidotes for Potentially Life-Threatening Drug Overdoses: Intravenous Lipid Emulsion

Roberts, James R. MD

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Author Credentials and Financial Disclosure:

James R. Roberts, MD, is the Chairman of the Department of Emergency Medicine and the Director of the Division of Toxicology at Mercy Health Systems, and a Professor of Emergency Medicine and Toxicology at the Drexel University College of Medicine, both in Philadelphia.

Dr. Roberts has disclosed that he is a member of the Speakers Bureau for Merck Pharmaceuticals. All other faculty and staff in a position to control the content of this CME activity have disclosed that they and their spouses/ life partners (if any) have no financial relationships with, or financial interests in, any commercial companies pertaining to this educational activity. Lippincott CME Institute, Inc. has identified and resolved all faculty and staff conflicts of interest regarding this educational activity.

Part 1 in a Series

Learning Objectives: After participating in this activity, the physician should be better able to:

1. Summarize the available experimental and human data for the use of ILE for selected drug overdoses for application in daily practice.

2. Devise a rationale for using intravenous lipid emulsion (ILE) for selected drug overdoses.

3. Generate a general protocol for using ILE for selected drug overdoses.

After EMS field interventions, emergency physicians usually have first crack at resuscitating a life-threatening drug overdose. Once reaching the hospital alive, most intentional overdoses survive with aggressive supportive care and concomitant tried-and-true antidotes, but some patients defy resuscitation by even the most perceptive and learned clinician.

Occasionally, EMS can save someone in the field who has arrested or is about to, buying the EP some precious time. If the hapless individual simply needs naloxone, EMS has almost finished the resuscitation endeavor. Unfortunately, those who die outside the hospital from a drug overdose have essentially no chance of survival. And some toxins, such a colchicine, exotic hydrocarbons, or paraquat, can't be reversed by anyone on the planet.

Figure. Mercy Philad...
Figure. Mercy Philad...
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Some potentially destined-to-be-fatal overdose scenarios require only simple respiratory support, such as benzodiazepines, antipsychotics, and opioids. If a ventilator is handy and venous access and the airway can be secured, few should die from these overdoses. Of course, hypoxic brain damage, pulmonary aspiration, renal failure, and ARDS are ubiquitous lethal side effects, and commonly go hand-in-hand with many fatal overdoses that don't succumb to the drug itself. There are also a few specific massive pharmaceutical overdoses, however, that are essentially a death sentence even when the patient arrives awake and talking. If one takes enough calcium channel blockers, beta blockers, or tricyclic antidepressants, the scene is often set for a lethal outcome once the bolus of toxin is swallowed, regardless of physician intervention.

This month's column begins a discussion of some novel antidotes that hold promise for reversing previously lethal overdoses. While the miraculous effects of naloxone and digifab are well referenced in the literature, the heroic antidotes described in my discussions lack scientific rigor, and are based mainly on theory and promising albeit scattered and anecdotal case reports. Nonetheless, the reputed antidotes appear to be helpful in otherwise desperate situations, and can be considered even when the specific offending pharmaceutical is unknown.

Intravenous Lipid Emulsion as Antidote Beyond Local Anesthetic Toxicity: A Systematic Review

Cave G, Harvey M

Acad Emerg Med

2009;16(9):815

This is an up-to-date summary on the efficacy of intravenous lipid emulsion (ILE) as antidote therapy outside the product's accepted and more commonly described use for local anesthetic toxicity. It's essentially a literature review of 14 animal trials, one human study, and four case reports. The authors review the use of ILE as a resuscitation antidote for a variety of drugs encountered as serious overdose in denizens of the ED. Since the initial reports by Weinberg in 1998 demonstrating the amelioration of bupivacaine-induced cardiotoxicity in animals and later miraculous saves in humans, there have been case reports on ILE's antidote properties in a variety of clinical scenarios. While not FDA approved for any antidote use, lipid emulsion is endorsed by anesthesia organizations in Europe such as the European Society of Regional Anaesthesia & Pain Therapy. American toxicologists are now beginning to take notice of this promising intervention. Some even suggest the selected empiric use of this nascent antidote given the minimal clinical experience to date. (Crit Care Med 2009;37[3]:1157).

ILE's postulated mechanism of action is the reduction of free drug levels and subsequent toxicity by expanding the liquid plasma phase availability, essentially acting as a large vascular lipid compartment, or pharmacologic sponge, to soak up lipid soluble toxin: the so-called lipid sink theory. Other possible benefits include inhibition of transport of drugs across membranes and facilitation of fatty acid transport into mitochondria. The result is postulated to be maintenance of normal cellular energy generation and increased inotropy in the poisoned myocardium.

The authors gleaned and summarized relevant animal and human studies on the use of ILE for toxicity from tricyclic antidepressants, verapamil, propranolol, atenolol, thiopentone, bupropion/lamotrigine, sertraline/ quetiapine, and organophosphates. Subsequent case reports have expanded the scope to include such noteworthy overdoses as haloperidol and bupropion alone.

Tricyclic Antidepressants: Studies demonstrate a lower mortality rate in rats administered the tricyclic antidepressant (TCA) clomipramine when ILE was compared with saline controls. Similar animal studies posited a beneficial result for amitriptyline toxicity. In these studies, animals were poisoned to the point of requiring cardiac compressions or intravenous epinephrine for cardiovascular collapse. To date, there is no extended human experience with ILE for TCAs, but the theoretical possibilities appear promising. In the only cited controlled human study, Intralipid resulted in an increase in plasma amitriptyline-nortriptyline levels vs. saline in healthy adults taking the therapeutic drug. The TCA is supposedly drawn from tissue and then trapped and neutralized in the fat emulsion complex. Serum levels of lipophilic drugs, therefore, are expected to increase with ILE. One wonders what this will do to the already mysterious and inscrutable postmortem toxicology analysis by the medical examiner.

Verapamil: In rat and canine studies, animals poisoned with verapamil fared better with ILE than with saline when they were poisoned with this potent calcium channel blocker. This type of overdose has a pharmacologic profile that lends theoretical credence to lipid rescue.

Beta Blockers: Animal studies have shown improved homodynamic parameters when subject animals were poisoned with the long-acting lipid soluble beta blocker, propranolol. Other beta blockers, such as atenolol, also seem fair game. See the table for anecdotal experience for carvedilol (Coreg) overdose in humans.

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Potential Uses for ILE

The authors summarize case reports touting successful resuscitation from cardiac arrest secondary to bupropion/ lamotrigine. Read an interesting report by Sirianni, et al. (Ann Emerg Med 2008;51[4]:412.) You will be impressed for sure. In most case reports, the theoretical antidote was withheld until the patient suffered cardiac arrest, including a need for cardioversion or CPR, and after the maximum use of other standard antidotes failed. Not all patients given ILE survived to discharge, perhaps a comment on the lack of universal success or the tardy use of the antidote after cardiac arrest had occurred.

Although the literature has support for the concept of ILE infusion, the efficacy has not been established with certainty. In a complex case report milieu when multiple antidotes and other supportive measures are simultaneously instituted and the exact overdose details are unknown, it's difficult to establish efficacy. In some case reports, the use of other resuscitative measures prior to failure has not been totally quantified. It is questionable, for example, whether the maximum dose of sodium bicarbonate or calcium was used in some of the TCA and calcium channel blocker reports.

The authors emphasize that ILE is safe and reasonable to use when no other antidote exists and the patient has failed maximum standard interventions. Theoretical value seems best for drugs with high lipophilicity and with toxins that are tissue-fixed and particularly difficult to dialyze or otherwise incapacitate in the serum.

The toxicity of this massive lipid load is unknown. ILE has been used for years for IV alimentation. There are no proven adverse effects from ILE used as a rescue antidote in humans. Given the rarity of fatal cases, a prospective controlled study would be difficult if not impossible to perform. Given the current status, the ethics of such a study is questionable. In general, there appears to be a consensus in the literature that ILE therapy can currently be considered “when patient deterioration is ongoing and life-threatening despite maximal available established therapy.” Of note, two registries exist for information and reporting individual cases, http://lipidrescue.org and www.lipidregistry.org.

A potential downside of rapid ILE infusion includes lung injury from a massive fat overload. The suggested protocols rapidly infuse a large volume of ILE, but the duration of therapy is truncated (about 30 minutes). If only an initial bolus is used, these may be recurrence of toxicity. (Anesth Analg 2009;108[4]:1062.)

Lipid Rescue Resuscitation from Local Anaesthetic Cardiac Toxicity

Weinberg G

Toxicol Rev

2006;25(3):139

This informative article by a premier investigator in lipid rescue therapy, Dr. Guy Weinberg from the University of Illinois in Chicago, details the use of ILE (Intralipid) for systemic local anesthetic toxicity. The article is included as a reference because many of the mechanisms and theories surrounding the antidote have been best studied with local anesthetic toxicity. The suggested regimen, termed “preliminary recommendations” for lipid rescue in severe local anesthetic toxicity, is outlined in the table. It would appear reasonable to use this as a starting base for the empiric use of ILE for other agents producing life-threatening toxicity.

Comment: The only readily available ILEs are Liposyn II and Intralipid, a milky substance given IV for nutritional support. The 20% concentration is suggested. Curiously, propofol and etomidate can be delivered with this product. Intralipid first found favor in the anesthesiology literature when a seemingly miraculous cure for bupivacaine overdose was published. Cardiac arrest following overdose of this local anesthetic was generally universally irreversible and recalcitrant to standard ACLS protocols. No specific antidote for bupivacaine exists. The case reports in the anesthesia literature (and now toxicology and EM literature) have been rather dramatic, although no placebo-controlled double-blind prospective trials have been performed in humans to my knowledge. One wonders how many cases have failed the use of this seemingly promising antidote. Our anesthesiologists now carry Intralipid on their resuscitation cart should a brachial plexus block go astray.

The theory behind Intralipid is intuitive. It is a lipid emulsion that sucks up any free drug that would otherwise be in the blood or bound to tissue, such as myocardium. While the theory behind it is quite plausible, the detailed pharmacokinetics and pharmacodynamics have yet to be unraveled. What does serum chock full of lipid emulsion do to other therapeutic drugs, such as some antiarrhythmics? Promising case reports show that Intralipid reverses overdoses from tricyclic antidepressants, bupropion, atypical antipsychotics, beta blockers, and calcium channel blockers, dramatically so for those who were circling the drain and not expected to survive. The calcium channel blocker, beta blocker, and TCA cases that no one can expect to resuscitate are academic and fodder for ILE rescue by tuned-in clinicians.

The recent American College of Medical Toxicology meeting had no less than seven presentations on this subject, essentially case reports describing isolated good outcomes. (See table.) Cases that have failed this intervention have not been widely promulgated.

Our toxicology consultant service has attempted Intralipid or Liposyn rescue in a handful of cases, and our experience is mixed. It is unclear exactly when to infuse the milky emulsion, but because it is relatively innocuous and safe, it would seem reasonable to institute this therapy sooner rather than later, certainly before cardiac arrest. One does not need to know the exact offending agent, but one can intuit a beta blocker, calcium channel blocker, or TCA overdose from the clinical picture. Of course, aggressive use of other standard antidotes or interventions should not be eschewed.

As a final note, if one is going to consider ILE as an antidote, it needs to be in the antidote section of your ED, not residing in the pharmacy to be summoned when needed or subject to the vagaries and logistics of delayed off-site availability. In our pharmacy, for example, all intravenous feeding supplements are mixed outside the hospital, and none was kept ready for emergency use. We have added Liposyn to the Pyxis. The ILE protocol does not yet appear in any nursing manual, and I don't know if there is an appreciable difference in efficacy between Intralipid and Liposyn.

The hope is that the well-described lifesaving benefit of ILE for bupivacaine may be generalized to other lipid-soluble toxins, making this a nifty general antidote, similar to oral activated charcoal. It is still not standard of care to consider ILE in a life-threatening overdose, and most EPs won't have much chance to use it. This one awaits further study before it goes mainstream. Those caveats offered, I can think of no good reason to avoid it when all else has failed or when your past experience and gut feeling tell you that everything that you intend to try will, in fact, fail. I am going to consider ILE for the next elderly patient with symptomatic bradycardia, hypotension, or heart block from inadvertent overmedication from his calcium channel blocker-beta blocker combination, at least initially in lieu of a prophylactic transvenous pacemaker.

Suggestion: Give it prior to cardiac arrest, and keep those case reports coming.

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ILE Abstracts from the 2009 North American Congress of Clinical Toxicology

Figure. Dr. Roberts ...
Figure. Dr. Roberts ...
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The following abstracts and case reports were presented at the recent toxicology meeting professing beneficial effects of ILE for treating various overdoses.

1. D Carr, et al: Following unsuccessful use of sodium bicarbonate and vasopressors, ILE, in a total dose of 100 grams over 90 minutes, resuscitated an 80-year-old man with an unstable doxepin (TCA) overdose.

2. D Carr, et al: A case report of the successful resuscitation of a 31-year-old woman ingesting the BB carvedilol (Coreg) who was unresponsive to saline, glucagon, calcium chloride, and dopamine. This was termed an extraordinary outcome in an unstable patient.

3. WT Hurley, et al: A poison center report of the use of ILE as an antidote to severe poisonings from carbamazepine, flecanide, hydroxychloroquine, bupivacaine, and bupropion. Cardiac arrest, seizures, and hypotension occurred prior to use, and four experienced a full recovery. The flecanide overdose patient died, attributed to late administration of the antidote.

4. TJ Meehan, et al: Report of a successful resuscitation of a patient with a carvedilol overdose despite the use of glucagon, insulin/glucose, and maximum dose of vasopressors. A return of circulation was noted within minutes of ILE infusion in two similar cases.

5. JJ Lu, et al: Report of dramatic QTC narrowing after ILE administration to a patient with cardiotoxicity from a quetiapine (Seroquel) overdose.

6. JA Oakes, et al: Report of a successful use of ILE in a patient ingesting diltiazem, who was unresponsive to standard therapies, including insulin/glucose and intraaortic balloon pump.

7. PL West, et al: A report of a benign massive ILE overdose (3265 mL) only resulting in extreme lipemic serum and interference of laboratory testing as a result of the antidote.

Source: Clin Toxicol 2009;47(7):701.

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Composition of Intravenous Lipid Emulsion (ILE)

* Available as Intralipid 20% or Liposyn II 20%.

* Sterile, non-pyrogenic 20% fat emulsion.

* Intravenous administration as source of calories and essential fatty acids.

* Composition: 20% soybean oil (Intralipid only), 10% safflower oil and 10% soybean oil (Liposyn only), 1.2% egg yolk phospholipids, 2.25%-2.5% glycerin, and water for injection.

* Sodium hydroxide added to adjust ph to 8 (Intralipid range: 6–8.9) or to 8.3 (Liposyn range: 6–9).

* Osmolality of approximately 350 mosmol/kg water (258–260 mosmol/liter of emulsion).

* Contains emulsified fat particles approximately 0.4–0.5 micron in size.

* Administer via peripheral vein or by central venous infusion.

* Supplied as sterile emulsion in varying fill sizes. Both: 250 mL and 500 mL. Intralipid also in 100 mL and 1000 mL; Liposyn also in 200 mL.

* Some preparations of propofol and etomidate use Intralipid as a vehicle.

* Adverse reactions reported during or after infusion: fever, chills, nausea, vomiting, headache, and back or chest pain with dyspnea and cyanosis.

* Not FDA approved as an antidote for drug overdose.

Sources: RxList: The Internet Drug Index and RxMed.

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Preliminary Strategies for Lipid Rescue in Severe Local Anesthetic Toxicity*

Infuse 20% ILE intravenous as:Bolus injection 1.5 mL/kg**Follow with continuous infusion 0.25 mL/kg/min for 30 min.

Repeat bolus one to three times every three to five minutes if no improvement.

Increase rate of infusion to 0.5 mL/kg/min for declining blood pressure.

* Can be extrapolated to other toxins. Continue other resuscitative efforts, including CPR.

**For initial dose, withdraw 100 mL from a 500 mL bag/bottle, and inject with a syringe. Then attach to infusion pump.

Source: Crit Care Med 2009;37(3);1157.

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Reader Feedback:

Readers are invited to ask specific questions and offer personal experiences, comments, or observations on InFocus topics. Literature references are appreciated. Pertinent responses will be published in a future issue. Please send comments to emn@lww.com.

Dr. Roberts: I read your article on hyperkalemia, and I noticed one of the treatments you advocate (along with others) is 1 amp D50 and 50 units of insulin. Is the dose of insulin correct? I usually give 1 amp D50 and 10 units of insulin. Am I undertreating or is that a typo? Thank you. Scott Goldstein, DO, Hershey, PA

Dr. Roberts responds: This is a typo, and 10 units of insulin is the preferred dose. The 50 got mixed up with 50 mL of 50% dextrose (1 ampule). I don't know how the 10 units of insulin originally came about; it's a very small dose, and it seems like someone simply made it up, and it stuck. Clearly dating myself, we used to give regular insulin in huge doses by today's standards (50 units IV and 50 units SC simultaneously) for DKA without problems of profound hypoglycemia. In addition, we are using 70-100 units of insulin IV per hour for calcium channel/beta blocker overdose, with minimal glucose supplementation. Best to stick, however, with 10 units of insulin and 1 ampule of 50% dextrose for hyperkalemia.

Dr. Roberts: I read your article on ECG findings for hyperkalemia. Great article. I wanted to re-emphasize a point you made. You made a comment about seeing bradycardia relatively often with hyperK cases in your practice, and I completely agree. I also agree that this is something that is taught too infrequently. I've seen at least a dozen cases of bizarre bradydysrhythmias and strange AV blocks with hyperK. I teach our residents that if you ever see a bradydysrhythmia that looks bizarre or “weird” or that doesn't respond to the usual ACLS drugs, that's probably hyperK.

I'm attaching a representative example. This patient (Figure 1) presented with an unstable bradycardia that was thought to be a very slow junctional rhythm. The physicians tried treating the patient using fairly standard ACLS measures: atropine, transcutaneous pacer, EPI, and even a transvenous pacer, but nothing worked. Then finally they got back a potassium value of 7.7. Then they gave calcium and 2 amps of sodium bicarbonate, and the patient immediately responded. (Figure 2.)

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We had yet another case a few months ago in which our staff and the cardiology service treated a patient for an unstable bradycardia (HR 40s, low BP) with the usual ACLS algorithm (atropine, transcutaneous pacer, and then dopamine), and just before putting in a transvenous pacer, the lab called back with a potassium value of 8.5. The patient responded to calcium and sodium bicarbonate. These patients are almost always severely acidotic, and the ACLS brady algorithm doesn't work in severely acidotic patients. Physicians should always consider severe hyperkalemia in patients with bradydysrhythmias. Thanks for your continued writing. — Amal Mattu, MD, Baltimore

Dr. Roberts responds: I agree that bradycardia is ubiquitous with hyperkalemia, and this is not stressed much in the literature. Another cause of ACLS-resistant bradycardia is an inadvertent excessive calcium channel blocker-beta blocker therapy, a common combination in the elderly who can easily become toxic by mistake. This month's column suggests that intravenous lipid emulsion (Intralipid) may be something to try before placing a pacemaker in such patients.

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CME Participation Instructions

To earn CME credit, you must read the article in Emergency Medicine News, and complete the evaluation questions and quiz, answering at least 80 percent of the questions correctly. Mail the completed quiz with your check for $12 payable to Lippincott Continuing Medical Education Institute, 530 Walnut Street, 8th Floor East, Philadelphia, PA 19106. Only the first entry will be considered for credit, and must be received by Lippincott Continuing Medical Education Institute by December 31, 2010. Acknowledgment will be sent to you within six to eight weeks of participation.

Lippincott Continuing Medical Education Institute is accredited by the Accreditation Council for Continuing Medical Education to provide medical education to physicians. Lippincott Continuing Medical Education Institute designates this educational activity for a maximum of 1 AMA PRA Category 1 Credit.™ Physicians should only claim credit commensurate with the extent of their participation in the activities.

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