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Three Part Question

In [patients who have hypotension or circulatory collapse following a tricyclic antidepressant overdose] does [lipid emulsion or standard therapy alone] lead to [lower mortality and fewer complications]?

Clinical Scenario

A thirty year old man is brought to the Emergency Department (ED) having called the ambulance claiming to have taken a massive overdose of amitriptyline. He is noted to be hypotensive and this remains refractory to intravenous fluids and sodium bicarbonate. You know that amitriptyline is lipid soluble and wonder whether lipid emulsion is likely to be of benefit.

Search Strategy

Ovid Medline 1950 - 2010 January Week 1
Ovid Embase 1980 - 2010 Week 02
(exp Antidepressive Agents, Tricyclic/ or tricyclic.mp. or amitriptyline.mp. or exp Amitriptyline/ or desipramine.mp. or exp Desipramine/ or clomipramine.mp. or exp Clomipramine/ or doxepin.mp. or exp Doxepin/ or dothiepin.mp. or exp Dothiepin/ or imipramine.mp. or exp Imipramine/ or lofepramine.mp. or exp Lofepramine/ or nortriptyline.mp. or exp Nortriptyline/ or trimipramine.mp. or exp Trimipramine/) AND (intralipid.mp. or exp Fat Emulsions, Intravenous/)

Search Outcome

The search retrieved 23 papers including 3 relevant animal studies and one study in healthy volunteers. There were no randomised controlled trials, cohort studies, case series or case reports of the use of lipid emulsion in the clinical environment.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Minton et al 1987 England	Four healthy volunteers aged 21-27 years who were given amitriptyline 75mg od for 10 days. On the 8th and 10th days they were cannulated and randomly assigned to receive either saline infusion or lipid emulsion (500ml Intralipid 20% given over 5h), with crossover design. Blood was taken prior to infusion, at 2h and 5h for levels of amitriptyline, its metabolite (nortriptyline) and lipids.	Prospective crossover randomised controlled volunteer study	Mean levels of amitriptyline + nortriptyline	13.8% higher at the end of lipid treatment compared to saline group (p>0.05)	Small numbers Therapeutic doses of amitriptyline given over 8 days - may perform differently in an acute overdose situation with ongoing gastric absorption and signs of toxicity
			Mean triglyceride concentration	500% increase in lipid emulsion group (p<0.005)

Comment(s)

Lipid emulsion is a promising treatment for tricyclic antidepressant overdose. Tricyclic antidepressants (TCAs) are lipid soluble. Some have postulated that lipid emulsion may reduce toxicity by creating an intravascular lipid compartment, into which lipid soluble drugs may be sequestered (Weinberg et al, 2003; Weinberg et al, 1998). Alternatively, lipid emulsion may work by enhancing free fatty acid availability for cardiac metabolism (Van der Velde et al, 1996). The only human data comes from a volunteer study, which demonstrated that lipid emulsion did not significantly alter TCA blood levels. Our search also identified three animal studies. Harvey et al (2009) demonstrated that lipid emulsion was superior to saline infusion for treatment of TCA-induced hypotension. The same group has also demonstrated that lipid emulsion is superior to sodium bicarbonate for treatment of TCA-induced hypotension in rabbits (Harvey et al, 2007). Finally, Yoav et al (2002) demonstrated that infusion of lipid emulsion resulted in lower mortality than saline infusion in TCA-intoxicated rats. The Lipid Rescue website (www.lipidrescue.org) also contains one informal case report of the successful use of lipid emulsion to treat refractory QRS prolongation in an intubated patient following TCA overdose. The ECG changes resolved after 4 hours and the patient recovered. In itself, this represents very weak evidence for the efficacy of lipid emulsion in this situation. Further, the patient developed haematuria after 4-5 hours and haemoglobin could not be estimated because of the lipaemic sample. Interference with laboratory assays and hypertriglyceridaemia are important side-effects of lipid emulsion. However, given the evidence presented and in the absence of stronger evidence, it would be reasonable to administer lipid emulsion to a patient with serious, life-threatening cardiotoxicity secondary to TCA overdose that is refractory to other measures.

Clinical Bottom Line

There is no evidence that lipid emulsion is of benefit as part of the standard treatment of TCA overdose in humans. However, given the results of three animal studies and a plausible physiological mechanism, lipid emulsion should be considered for life-threatening cardio-toxicity that is refractory to other measures following TCA overdose.

Level of Evidence

Level 3 - Small numbers of small studies or great heterogeneity or very different population.

References

1. Minton NA; Goode AG; Henry JA The effect of a lipid suspension on amitriptyline disposition Archives of Toxicology 1987; 60(6): 467-469
2. Harvey M; Cave G; Hoggett K Correlation of plasma and peritoneal diasylate clomipramine concentration with haemodynamic recovery after intralipid infusion in rats Academic Emergency Medicine 2009; 16(2): 151-156
3. Harvey M; Cave G Intralipid outperforms sodium bicarbonate in a rabbit model of clomipramine toxicity Annals of Emergency Medicine 2007; 49(2): 178-185
4. Yoav G; Odelia G; Shaltiel C A lipid emulsion reduces mortality from clomipramine overdose in rats Veterinary and Human Toxicology 2002; 44(1): 30
5. Van der Velde M; Woutens PF; Rolf N; Van Aken H; Flameng W; Vandermeersch E Long-chain triglycerides improve recovery from myocardial stunning in conscious dogs Cardiovascular Research 1996; 32: 1008-1015
6. Weinberg G; VadeBoncouer T; Ramaraju GA; Garcia-Amaro AF; Cwik MJ Pretreatment or resuscitation with a lipid infusion shifts the dose-response to bupivacaine-induced asystole in rats Anaesthesiology 1998; 88: 1071-1075
7. Weinberg G; Ripper R; Feinstein DL; Hoffman W Lipid emulsion infusion rescues dogs from bupivacaine induced cardiac toxicity Regional Anesthesia and Pain Medicine 2003; 28: 198-202