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doi: 10.1097/ACC.0b013e3182a526fa
Case Reports: Case Report

Two Lessons from the Empiric Management of a Combined Overdose of Liraglutide and Amitriptyline

Bowler, Matthew BSc, MBChB, MRCPCH; Nethercott, Daniel Robert BSc, MBBCh, FRCA, DICM, FFICM

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Author Information

From the Department of Anaesthetics, North West School of Anaesthesia, Manchester; and Anaesthesia and Critical Care Medicine, Royal Bolton Hospital, Bolton, United Kingdom.

Accepted for publication June 25, 2013.

Funding: No funding required.

The authors declare no conflicts of interest.

Address correspondence to Matthew Bowler, BSc, MBChB, MRCPCH, Department of Anaesthetics, Royal Bolton Hospital, Minerva Road, Farnworth, Bolton, Lancashire BL4 0JR. Address e-mail to Bowler.Matthew@Gmail.com.

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Abstract

We report the case of a 52-year-old man with a combined liraglutide and amitriptyline overdose who presented with a seizure and then pulseless electrical activity cardiac arrest. This is the largest reported overdose of liraglutide (36 mg), a novel glucagon-like peptide-1 analog recommended for certain patients with type 2 diabetes mellitus. The subsequent biochemical effects included severe electrolyte disturbances associated with polyuria. Regarding the amitriptyline, treatment with lipid emulsion correlated with resolution of electrocardiographic changes and successful resuscitation. The treatment of amitriptyline overdose with lipid emulsion is briefly discussed.

We present the case of a combined overdose of amitriptyline and the long-acting glucagon-like peptide-1 analog liraglutide. The case was managed empirically including an initial loading dose of lipid emulsion (Intralipid 20%) and subsequent admission to intensive care. Apparent resolution of the electrocardiographic changes associated with amitriptyline overdose was seen with use of lipid emulsion. The biochemical consequences of the largest dose of liraglutide reported are also described.

Signed consent was obtained from the patient for publication of this report.

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CASE DESCRIPTION

A 52-year-old man presented to the emergency department, having injected 36 mg of liraglutide subcutaneously and ingested an unknown number of amitriptyline tablets. The usual daily dose of liraglutide is 1.2 mg. He had a medical history of depression, alcoholic liver disease, osteoporosis, exocrine pancreatic insufficiency, previous peptic ulcer disease and vagotomy, and B12 deficiency but was not a diabetic, the liraglutide having been prescribed to his partner. He was found by his wife at 2230 with the empty amitriptyline pill cases and liraglutide syringe, and an ambulance was promptly called. The patient suffered 3 grand mal seizures on route to hospital, successfully managed with two 5 mg doses rectal diazepam. On admission to the Emergency Department (1 hour after being found), he registered a Glasgow Coma Score of 3. He was hypotensive (noninvasive arterial blood pressure of 94/64 mm Hg) and apneic, requiring bag-mask ventilation. Shortly after his arrival, he suffered a pulseless electrical activity cardiac arrest, which was treated with cardiopulmonary resuscitation (CPR) including a single dose of 1 mg IV epinephrine. Ventricular tachycardia with a palpable pulse was recorded after 2 minutes of CPR, prompting a single synchronized direct current shock (150 J), but then became pulseless ventricular tachycardia. A further 2 minutes of CPR were provided including the administration of sodium bicarbonate, 10 mL of 10% calcium chloride, and tracheal intubation. After a further shock at 150 J, there was resumption of spontaneous circulation. His blood glucose was 5.6 mmol/L (100 mg/dL), and arterial blood gas analysis showed a severe metabolic acidosis with a lactate of 13.7 mmol/L. A postarrest 12-lead electrocardiogram showed broad QRS complexes (Fig. 1). Given the life-threatening features of cardiac instability, severe acid–base disturbance, and persisting hypotension (noninvasive arterial blood pressure 60/39 mm Hg), an initial loading dose of 100 mL of 20% lipid emulsion (Intralipid) was given as advised by Toxbase.1 The QRS complexes normalized, and the patient’s arterial blood pressure increased to 116/64 mm Hg (without any vasoactive support) almost immediately after the loading dose of lipid emulsion (Fig. 2).

Figure 1
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Figure 2
Figure 2
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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.

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DISCUSSION

Liraglutide

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.

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Lipid Emulsion for Amitriptyline 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.

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REFERENCES

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.

4. National Institute. of Clinical Excellence. . TA203 Liraglutide for the treatment of type 2 diabetes mellitus 2010. Available at: http://publications.nice.org.uk/liraglutide-for-the-treatment-of-type-2-diabetes-mellitus-ta203. Accessed July 14, 2012.

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

7. Novo Nordisk. . Victoza 6 mg/ml solution for injection in pre-filled pen. Available at: http://www.medicines.org.uk/emc/medicine/21986/SPC/Victoza. Accessed October 28, 2012

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

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