Despite the normal serum glucose, treatment with glucagon was also given as a single dose of 8 mg; this was done empirically and based on unfamiliarity with the effects of liraglutide. Repeated blood glucose measurements in the periresuscitation period were all within normal limits, including that recorded in the patient’s home by paramedic staff. Admission to intensive care and general supportive measures were instituted including mechanical ventilation. Therapeutic hypothermia as part of postcardiac arrest care was considered but not instituted, given the unknown effects of the liraglutide. Profound hypophosphatemia (with a nadir serum concentration of <0.32 mmol/L) required repeated IV doses of phosphate to correct to normal levels. A diuresis occurred over the subsequent 12 hours (peak urine production 13 mL/kg/h) associated with a low urine osmolality (nadir of 95 mOsm/kg), hypernatremia (peak of 152 mmol/L), hypokalemia (nadir of 3.0 mmol/L), and a serum osmolality of 318 mOsm/kg. The patient responded to further general supportive measures and was discharged from hospital 26 days later. Telephone follow-up several months later found him to have normal physical and functional status but having made further attempts at suicide and self-harm.
Liraglutide is a novel glucagon-like peptide-1 receptor agonist that mimics incretin and helps to maintain glucose homeostasis through stimulation of glucose-mediated insulin secretion and inhibition of glucagon release in a glucose-dependent manner.2 Additional therapeutic effects include increased satiety and weight loss.3 The United Kingdom National Institute for Health and Clinical Excellence recommends liraglutide as part of a triple therapy regime for diabetics with poor glycemic control, obesity, or where insulin therapy is contraindicated.4 The main side effects are gastrointestinal disturbance, headache, and dizziness.5,6 Product information from Novo Nordisk reports an overdose of 17.5 mg resulting in severe nausea and vomiting, no episodes of hypoglycemia, and recovery without complication.7 Our report also suggests that liraglutide does not appear to cause hypoglycemia even in large overdose.
Evidence for the efficacy of lipid emulsion use in treating overdose with tricyclic antidepressants (TCA) is inconclusive. Lipid emulsion has been reported to reduce systemic toxicity caused by lipophilic drugs, with proposed mechanisms including the lipid sink model,8 carnitine metabolism theory,9 and calcium agonist theory.10
There are a number of case reports showing therapeutic benefit of lipid emulsion in TCA overdose.11–14 Engels and Davidow11 administered Intralipid 5 hours after intoxication following cardiac arrest and other resuscitation drugs, with resultant reduction in lactate, vasopressor requirements, and eventual patient survival. Similarly, Huge et al.12 began administration of lipid after 60 minutes of CPR with almost immediate return of spontaneous cardiac output. Harvey and Cave13 report a multidrug overdose involving amitriptyline with both increased arterial blood pressure and sequestration of the lipophilic amitriptyline. Blaber et al.14 report a 2.25 g dothiepine overdose with significant cardiovascular and neurological abnormalities, resulting in a cardiac arrest. Subsequent administration of a loading dose of lipid emulsion led to immediate correction of the broad complex rhythm to normal. Many other standard therapies (such as sodium bicarbonate and adrenaline) had been administered without effect in these and in our case.
A small study of volunteers given amitriptyline and then lipid emulsion showed a nonsignificant trend to higher plasma concentrations of amitriptyline after lipid treatment with apparent intravascular sequestration, providing some support for the lipid sink model.15 However, the doses observed were much lower than commonly seen in patients after an overdose. A number of animal studies investigating the effect of lipid emulsion use in TCA toxicity have reported increased arterial blood pressure and decreased volume of distribution of the TCA16 and correction of the QRS prolongation17 in rabbits and reduced mortality in rats.18 However, lipid infusion had no effect on hemodynamics in a porcine model of TCA overdose.19 A systematic review across a range of drugs has judged it reasonable to use lipid emulsion for TCA overdose after other supportive measures have failed, although cautions on the lack of good quality evidence and safety data.20
The clinicians involved in our case were convinced that the administration of lipid emulsion caused an almost immediate resolution of the life-threatening features of amitriptyline overdose and considered that the risk-benefit balance would favor its use in such circumstances. This judgment is highly prone to personal bias, and case studies cannot separate the effects of one drug from those of other resuscitative drugs and strategies, particularly in such complex circumstances involving a second, relatively unknown drug. Given the mechanism of action of liraglutide, we also assume that the severe electrolyte disturbances seen in the intensive care unit were related to this drug, although this single observation provides no certainty.
1. National Poisons Information Service. . Toxbase. Available at: http://www.toxbase.org
. Accessed November 8, 2012
2. Peters K. Liraglutide for the treatment of type 2 diabetes: a clinical update. Am J Ther. 2011;20:1075–2765
3. Nauck M. Incretin-based therapies for type 2 diabetes mellitus: properties, functions, and clinical implications. Am J Med. 2011;124(1 Suppl):S3–S18.
5. Marre M, Shaw J, Brandle M, Bebakar WMW, Kamaruddin NA, Strand J, Zdravkovic, Le Thi TD, Colagiuri S. Liraglutide, a once-daily human GLP-1 analogue, added to a sulphonylurea over 26 weeks produces greater improvements in glycaemic and weight control compared with adding rosiglitazone or placebo in participants with type 2 diabetes (LEAD 1 SU). Diabet Med. 2009;26:268–78
6. Russell-Jones D, Vaag A, Schmitz O, Sethi BK, Lalic N, Antic S, Zdravkovic M, Ravn GM, Simó R. Liraglutide vs insulin glargine and placebo in combination with metformin and sulfonylurea therapy in type 2 diabetes mellitus (LEAD-5 met+SU): a randomised controlled trial. Diabetologia. 2009;52:2046–55
8. Weinberg G, Lin B, Zheng S, Di Gregorio G, Hiller D, Ripper R, Edelman L, Kelly K, Feinstein D. Partitioning effect in lipid resuscitation: further evidence for the lipid sink. Crit Care Med. 2010;38:2268–9
9. Weinberg GL, Palmer JW, VadeBoncouer TR, Zuechner MB, Edelman G, Hoppel CL. Bupivacaine inhibits acylcarnitine exchange in cardiac mitochondria. Anesthesiology. 2000;92:523–8
10. Huang JM, Xian H, Bacaner M. Long-chain fatty acids activate calcium channels in ventricular myocytes. Proc Natl Acad Sci U S A. 1992;89:6452–6
11. Engels PT, Davidow JS. Intravenous fat emulsion to reverse haemodynamic instability from intentional amitriptyline overdose. Resuscitation. 2010;81:1037–9
12. Huge V, Baschnegger H, Moehnle P, Peraud A, Briegel J. Amitriptyline-induced cardiac arrest: treatment with fat emulsion. Anaesthesist. 2011;60:541–5
13. Harvey M, Cave G. Case report: successful lipid resuscitation in multi-drug overdose with predominant tricyclic antidepressant toxidrome. Int J Emerg Med. 2012;5:8
14. Blaber MS, Khan JN, Brebner JA, McColm R. “Lipid rescue” for tricyclic antidepressant cardiotoxicity. J Emerg Med. 2012;43:465–7
15. Minton NA, Goode AG, Henry JA. The effect of a lipid suspension on amitriptyline disposition. Arch Toxicol. 1987;60:467–9
16. Harvey M, Cave G, Hoggett K. Correlation of plasma and peritoneal diasylate clomipramine concentration with hemodynamic recovery after intralipid infusion in rabbits. Acad Emerg Med. 2009;16:151–6
17. Harvey M, Cave G. Intralipid outperforms sodium bicarbonate in a rabbit model of clomipramine toxicity. Ann Emerg Med. 2007;49:178–85
18. Yoav G, Odelia G, Shaltiel C. A lipid emulsion reduces mortality from clomipramine overdose in rats. Vet Hum Toxicol. 2002;44:30
19. Litonius E, Niiya T, Neuvonen PJ, Rosenberg PH. No antidotal effect of intravenous lipid emulsion in experimental amitriptyline intoxication despite significant entrapment of amitriptyline. Basic Clin Pharmacol Toxicol. 2012;110:378–83
20. Jamaty C, Bailey B, Larocque A, Notebaert E, Sanogo K, Chauny JM. Lipid emulsions in the treatment of acute poisoning: a systematic review of human and animal studies. Clin Toxicol (Phila). 2010;48:1–27