Journal Club Synopsis November 2013

Lipid Rescue Therapy in Overdose

Many thanks to Abhi and Mala Katiyar for hosting and for the delicious south of the border feast!

Outstanding synopses, analysis, and additional review of the topic by Natalie K, Theresa, John P, Nick, Brian F, and Katie I.

Introduction:

Journal Club at the home of a toxicologist calls for a tox topic...in this case the use of lipid emulsion therapy to treat overdose.  IV lipid emulsions are usually thought of as part of nutritional support (TPN), but case reports of lipid emulsions used as rescue therapy for acute cardiotoxicity from lipophilic drug overdose in humans have been published since 2006.  We’ll call it LRT, or lipid resuscitation therapy moving forward, after the American College of Medical Toxicology guidelines.

Which overdoses?  Most compelling literature in overdose from local anesthetics, (LA) especially bupivacaine.  Also used in other lipophilic drug overdoses including calcium channel and beta blockers, TCAs and other antidepressants.

Mechanism?  3 are proposed:  enhancement of myocardial fatty acid transport  (preferred energy substrate of the heart), expanded intravascular lipid phase or “lipid sink” that alters the volume of distribution of the lipophilic toxin, and restoring cellular calcium transport/function.   Nobody knows for sure.

Risk?  Lipemia (who cares, except temporarily renders some lab results invalid), also possible acute lung injury although low incidence of this in patients receiving nutritional lipids, and critically ill patients after overdose already predisposed to acute lung injury. Need more experience to define scope and degree of risk.

When to use?   Great question.  American College of Medical Toxicology has a guideline that states “there are no standard of care requirements to use, or to choose not to use, LRT.  However, in circumstances where there is serious hemodynamic or other instability from a xenobiotic with a high degree of lipid solubility, LRT is viewed as a reasonable consideration for therapy, even if the patient is not in cardiac arrest.”  This actually is a protective document, allowing clinicians the choice of using/not using without declaring a medicolegally binding standard of care.  AHA 2010 ECC guidelines describe the use of LRT for specifically for LA toxicity.  There are reports of patients responding even after prolonged (up to 52 minutes) of cardiac arrest with LA toxicity.

Dose?  All over the place in the case reports...boluses, drips, repeat boluses.  The American College of Med Tox guidelines recommend 1.5 ml/kg bolus of 20% lipid emulsion over 2-3 minutes IV followed by infusion at a rate of 0.25 ml/kg/minute, with shortest duration of treatment possible until hemodynamic stability restored.  The room at JC agreed that using in unstable patients (not just those in overt cardiac arrest) seems reasonable, and LRT should be initiated immediately in LA toxicity.  There was some support for earlier administration in other overdoses, but concern that early LRT might delay treatment with more accepted therapies, and giving in anticipation of instability may result in unnecessary treatment and possible unnecessary complications.  It is reported that in bupivicaine toxicity, epinephrine administration is associated with a negative outcome, and reduces the efficacy of LRT (maybe because epi irritating to the heart?).  Therefore, as epinephrine hasn’t been shown to help in cardiac arrest anyway, consider avoiding epi or giving a smaller dose in the patient with a LA overdose.

Article 1:  Bologa C, et al.  Lipid Emulsion Therapy in Cardiodepressive syndrome after Diltiazem Overdose-a case report.  Am J Emerg Med. 2013;31:1154e3-1154e4.

Case report of 81 yo female who ingested 5.7 gm of diltiazem in a suicide attempt.  Even after gastric lavage, charcoal, calcium, hyperinsulin/euglycemia, epi drip and aggressive IV fluids patient remained hemodynamically unstable with a Mobitz II second degree AV block.   She received intralipid infusion and become hemodynamically and metabolically stable within 24 hours, and was ultimately discharged home neurologically intact.  Lots of missing information from this case report, but this patient appeared to have a positive outcome temporally related to the intralipid infusion.

Article 2:  Geib AJ, Liebelt E, Manini AF for the Toxicology Investigators’ Consortium (ToxIC). Clinical Experience with Intravenous Lipid Emulsion for Drug-Induced Cardiovascular Collapse.  J Med Toxicol 2012;8:10-14.

This retrospective chart review described the presentation and management of 9 cases of drug-induced cardiovascular collapse  (cardiac arrest or refractory shock) treated with LRT from 45 centers in 2.5 years.  Five patients (55%) met the main outcome of survival to hospital discharge.  Interestingly there was no significant increase in MAP immediately after LRT infusion (would expect increase in MAP if LRT helps contractility).  A number of possible adverse effects were described, but the scoring system used to assign causality to these events has been faulted as an inappropriate instrument for this purpose.  Again, lots of missing information regarding additional treatments and LRT dosing, no comparison group, and a very small retrospective study.  Also comment that this is likely an incomplete picture of the experience for this number of centers.

Article 3:  Presley JD, Chyka PA.  Intravenous Lipid Emulsion to Reverse Acute Drug Toxicity in Pediatric Patients.  Ann Pharmacother.  2013;47:735-743.

Moving to kids, this article is a brief description of 14 case reports of pediatric patients who received LRT to treat acute drug toxicity (7 cases of LA, 7 from other drugs (Ca channel blockers and other psych drugs).  Thirteen patients did well, one died.  One patient developed hypertriglyceridemia and pancreatitis.  Again, different dosing regimens.

Impressive how well LRT worked in the local anesthetic cases.  Patients received usual ACLS care with successful resuscitation from cardiac instability/cardiac arrest, and in one case resolution of V Tach using only LRT.  As anticipated, the nonanesthetic medication cases were more complicated, and information regarding additional treatment was incomplete.

Sobering that 20 cc of misplaced local anesthetics in 2 teenagers undergoing routine surgeries led to V tach and cardiac arrest.   A plea to be calculate maximum safe doses of local anesthetics, especially in small kids.

Also, point raised that for all of these articles, there is likely significant reporting bias.  Case reports are more likely to be written up and published when they are positive, especially with dramatic outcomes.  A skewed picture results.

EBM teaching point:  You’re not going to find many RCTs in the tox literature.  There are challenges in coordinating trials across multiple centers for what are often sporadic/rare ingestions, and currently there isn’t a good system to organize these research efforts.  Therefore, the level of evidence for many tox questions is low.  A generally accepted hierarchy of levels of evidence is below, and case reports are close to the bottom, but this is what we have to work with for this topic.

Interesting discussion at the end of JC about whether or not we’ve reached clinical equipoise on the question of the use of LRT for LA and other overdoses.  The problem with a drug such as LRT being used without controlled study is that by the time many case reports are published, the genie is out of the bottle.  Consensus in the room was that IRBs would not approve a RCT for LRT in LA use (eg bupivacaine), but that given the weak evidence for LRT in other ingestions (eg calcium channel blockers), there should be further study, ideally through a RCT.  Simply hoping that it might work as a last ditch isn’t a good reason to use it, and medical history is littered with examples of initially popular therapies ultimately shown to have no benefit (or to cause harm).   Even if this is beyond the point of IRB approval for a RCT, it was suggested that a more comprehensive review of national Tox center data would provide a less biased data set than continued publication of case reports.  A plug to call and report all tox cases to Poison Control, even if you are comfortable with management!