Comparison of Intravenous Lipid Emulsion, Bicarbonate, and Glucagon Treatments in a Rabbit Model of Clomipramine Toxicity

Background: This experimental study aimed to evaluate intravenous lipid emulsion, sodium bicarbonate, and glucagon as treatment options for the cardiotoxicity associated with clomipramine, a tricyclic antidepressant, and the antidotal effects of these drugs. Methods: In this experimental study, female and male New Zealand rabbits were divided into a sham group, a sodium bicarbonate treatment group, an intravenous lipid emulsion treatment group, and a glucagon treatment group. After the administration of a single dose of oral clomipramine (70 mg/kg), through an orogastric tube, vital parameters such as mean arterial pressure and oxygen saturation were measured, using a bedside monitor. Intoxication was established after the mean arterial pressure decreased to 40%-45%, within approximately 30-45 minutes. Treatments were administered after intoxication was established. Results: Although the mean arterial pressure values significantly changed over time in the sham and glucagon treatment groups, no significant changes were observed in the intravenous lipid emulsion and sodium bicarbonate treatment groups. Significant differences were observed among the values at 0 min compared with 30, 60, and 120 min in both the sham and the glucagon treatment groups. The clomipramine level changed significantly in all groups. Conclusion: Tricyclic antidepressant poisoning remains a difficult therapeutic challenge. Glucagon, a lipophilic drug, appears to be a promising candidate for the treatment of clomipramine-induced cardiotoxicity and should be considered early for the treatment of severe tricyclic antidepressant overdose.

TCA intoxication, Glucagon, Sodium bicarbonate, Intravenous lipid emulsion, Antidotes

[1] Liebelt EL. Cyclic antidepressants. In: Goldfrank’s Toxicologic Emergencies. 10th edition. Hoffman RS, Howland M, Lewin NA, Nelson LS, Goldfrank LR, editors. United States: McGraw-Hill. 2015;pp:972–982

[2] Wilson, M, Tripp J. Clomipramine. In: StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; 2020. Available at: https://www.ncbi.nlm.nih.gov/books/NBK541006/. Accessed March 25, 2020.

[3] Tay E, Sotiriou A, Graham GG, Wilhelm K, Snowden L, Day RO. Restarting antidepressant and antipsychotic medication after intentional overdoses: need for evidence-based guidance. Ther Adv Psychopharmacol. 2019;9:2045125319836889.

[4] Nelson LS, Erdman AR, Booze LL, Cobaugh DJ, Chyka PA, Woolf AD, et al. Selective serotonin reuptake inhibitor poisoning: An evidence-based consensus guideline for out-of-hospital management. Clin Toxicol (Phila). 2007;45:315-32.

[5] Body R, Bartram T, Azam F, Mackway-Jones K. Guidelines in Emergency Medicine Network (GEMNet): guideline for the management of tricyclic antidepressant overdose. Emerg Med J. 2011;28:347-68.

[6] Chan CY, Waring WS. Images in cardiovascular medicine. Tri-cyclic cardiotoxicity treated with sodium bicarbonate. Circulation. 2007;115:63–64.

[7] Kerr GW, McGuffie AC, Wilkie S. Tricyclic antidepressant overdose: a review. Emerg Med J. 2001;18:236.

[8] Ferraiolo A, Bordone C, Ramone A, et al. Universal versus risk factor screening for gestational diabetes mellitus. Clinical and experimental obstetrics & gynecology, 2018;45:53-57.

[9] Rombach SM, Wesselink EJ, de Stoppelaar EI, Rijnsburger ER, Slagt

C. Glucagon in hemodynamic instability after tricyclic antidepressant overdose. Netherlands Journal of Critical Care. 2016;24:25-27.

[10] Perichon D, Turfus S, Gerostamoulos D, Graudins A. An assessment of the in vivo effects of intravenous lipid emulsion on blood drug concentration and haemodynamics following oro-gastric amitripty-line overdose. Clin Toxicol (Phila). 2013;51:208-15.

[11] Mottram AR, Bryant SM, Aks SE. Dose-dependent response to cyclodextrin infusion in a rat model of verapamil toxicity. West J Emerg Med. 2012;13:63-7.

[12] R Core Team (2019). R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. URL https://www.R-project.org/.

[13] Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. Journal of the Royal Statistical Society Series B, 1995;57:289–300. http://www. jstor.org/stable/2346101.

[14] Thanacoody HK, Thomas SH. Tricyclic antidepressant poisoning :cardiovascular toxicity. Toxicol Rev. 2005;24:205-14.

[15] Vrijlandt PJ, Bosch TM, Zijlstra JG, Tulleken JE, Ligtenberg JJ, van der Werf TS. Sodium bicarbonate infusion for intoxication with tricyclic antidepressives: recommended in spite of lack of scientific evidence. Ned Tijdschrift Geneesk. 2001;145:1686-99.

[16] Kaplan YC, Hocaoglu N, Oransay K, Kalkan S, Tuncok Y. Effect of glucagon on amitriptyline-induced cardiovascular toxicity in rats. Hum Exp Toxicol. 2008;27:321-5.

[17] Eyer F, Stenzel J, Schuster T, Felgenhauer N, Pfab R, von Bary C, et al. Risk assessment of severe tricyclic antidepressant overdose. Hum Exp Toxicol. 2009;28:511–19.

[18] Harvey M, Cave G. Intralipid outperforms sodium bicarbonate in a rabbit model of clomipramine toxicity. Ann Emerg Med. 2007;49:178-85.

[19] Cave G, Harvey M, Shaw T, Damitz R, Chauhan A. Comparison of intravenous lipid emulsion, bicarbonate, and tailored liposomes in rabbit clomipramine toxicity. Acad Emerg Med. 2013;20:1076-9.

[20] Paksu S, Duran L, Altuntas M, Zengin H, Salis O, Ozsevik S, et al. Amitriptyline overdose in emergency department of university hospital: Evaluation of 250 patients. Hum Exp Toxicol. 2014;33(9):980–90.

[21] Power BM, Hackett LP, Dusci LJ, Ilett KF. Antidepressant Toxicity and the Need for Identification and Concentration Monitoring in Overdose. Clin Pharmacokinet. 1995;29:154-71.

[22] Lavonas EJ, Drennan IR, Gabrielli A, Heffner AC, Hoyte CO, Orkin AM, et al. Part 10: Special Circumstances of Resuscitation: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2015;132:501-18.

[23] 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.

[24] Weinberg GL. Lipid emulsion infusion: resuscitation for local anesthetic and other drug overdose. Anesthesiology. 2012;117:180-7.

[25] Sensky PR, Olczak SA. High dose intravenous glucagon in severe tricyclic poisoning. Postgrad Med J. 1999;75:611-2.

[26] Teece S, Hogg K. Glucagon in tricyclic overdose. Emerg Med J. 2003;20:264-5.

[27] Brown TCK. Tricyclic antidepressant overdosage: experimental studies on the management of circulatory complications. Clin Toxicol. 1976;9:255-72.

[28] McCabe JL, Cobaugh DJ, Menegazzi JJ, Fata J. Experimental tricyclic antidepressant toxicity: a randomized, controlled com-parison of hypertonic saline solution, sodium bicarbonate, and hyperventilation. Ann Emerg Med. 1998;32:329-33.

[29] Bruccoleri RE, Burns MM. A Literature Review of the Use of Sodium Bicarbonate for the Treatment of QRS Widening. J Med Toxicol. 2016;12:121-9.