Calcium channel blocker poisoning
- Fermin Barrueto, Jr, MD, FACEP, FAAEM, FACMT
Fermin Barrueto, Jr, MD, FACEP, FAAEM, FACMT
- Clinical Associate Professor
- University of Maryland School of Medicine
Calcium channel blockers (CCBs) are used in the treatment of hypertension, angina pectoris, cardiac arrhythmias, and other disorders. These medications are available in both immediate-release and extended-release preparations; the latter are in wide clinical use (figure 1) .
The potential toxicity of these agents is substantial, and is often under appreciated by the public. As an example, over 9500 cases of CCB intoxication, caused by intentional or unintentional overdosage, were reported to poison centers in the United States during 2002 . Although only 16 percent of all cardiovascular drug exposures were due to CCBs, this class accounted for 38 percent of deaths .
The management of CCB intoxication will be reviewed here. A summary table to facilitate emergent management is provided (table 1). An overview of the major side effects of CCBs is presented separately. (See "Major side effects and safety of calcium channel blockers".)
The calcium channel blockers (CCBs) can be divided into two major categories based upon their predominant physiologic effects: the dihydropyridines, which preferentially block the L-type calcium channels in the vasculature; and the nondihydropyridines, such as verapamil and diltiazem, which selectively block L-type calcium channels in the myocardium [1,3].
The L-type calcium channels are responsible for myocardial contractility and vascular smooth muscle contractility; they also affect conducting and pacemaker cells. The dihydropyridines (including nifedipine, amlodipine, felodipine, nicardipine, nisoldipine, isradipine, and lacidipine) are potent vasodilators that have little negative effect upon cardiac contractility or conduction at standard doses. In contrast, verapamil and, to a lesser extent, diltiazem are weak vasodilators but have a depressive effect on cardiac conduction and contractility .
- Eisenberg MJ, Brox A, Bestawros AN. Calcium channel blockers: an update. Am J Med 2004; 116:35.
- Watson WA, Litovitz TL, Rodgers GC Jr, et al. 2002 annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med 2003; 21:353.
- Katz AM. Cardiac ion channels. N Engl J Med 1993; 328:1244.
- Hofer CA, Smith JK, Tenholder MF. Verapamil intoxication: a literature review of overdoses and discussion of therapeutic options. Am J Med 1993; 95:431.
- McAllister RG Jr, Hamann SR, Blouin RA. Pharmacokinetics of calcium-entry blockers. Am J Cardiol 1985; 55:30B.
- Sporer KA, Khayam-Bashi H. Acetaminophen and salicylate serum levels in patients with suicidal ingestion or altered mental status. Am J Emerg Med 1996; 14:443.
- Spurlock BW, Virani NA, Henry CA. Verapamil overdose. West J Med 1991; 154:208.
- Levine M, Boyer EW, Pozner CN, et al. Assessment of hyperglycemia after calcium channel blocker overdoses involving diltiazem or verapamil. Crit Care Med 2007; 35:2071.
- St-Onge M, Dubé PA, Gosselin S, et al. Treatment for calcium channel blocker poisoning: a systematic review. Clin Toxicol (Phila) 2014; 52:926.
- Ashraf M, Chaudhary K, Nelson J, Thompson W. Massive overdose of sustained-release verapamil: a case report and review of literature. Am J Med Sci 1995; 310:258.
- Thompson AM, Robins JB, Prescott LF. Changes in cardiorespiratory function during gastric lavage for drug overdose. Hum Toxicol 1987; 6:215.
- Thanacoody R, Caravati EM, Troutman B, et al. Position paper update: whole bowel irrigation for gastrointestinal decontamination of overdose patients. Clin Toxicol (Phila) 2015; 53:5.
- Tenenbein M. Position statement: whole bowel irrigation. American Academy of Clinical Toxicology; European Association of Poisons Centres and Clinical Toxicologists. J Toxicol Clin Toxicol 1997; 35:753.
- Tenenbein M, Cohen S, Sitar DS. Whole bowel irrigation as a decontamination procedure after acute drug overdose. Arch Intern Med 1987; 147:905.
- Proano L, Chiang WK, Wang RY. Calcium channel blocker overdose. Am J Emerg Med 1995; 13:444.
- Kerns W 2nd, Kline J, Ford MD. Beta-blocker and calcium channel blocker toxicity. Emerg Med Clin North Am 1994; 12:365.
- Isbister GK. Delayed asystolic cardiac arrest after diltiazem overdose; resuscitation with high dose intravenous calcium. Emerg Med J 2002; 19:355.
- Lam YM, Tse HF, Lau CP. Continuous calcium chloride infusion for massive nifedipine overdose. Chest 2001; 119:1280.
- DeRoos F. Calcium channel blockers. In: Goldfrank's Toxicologic Emergencies, 8th, McGraw-Hill, New York 2006.
- Sim MT, Stevenson FT. A fatal case of iatrogenic hypercalcemia after calcium channel blocker overdose. J Med Toxicol 2008; 4:25.
- Bailey B. Glucagon in beta-blocker and calcium channel blocker overdoses: a systematic review. J Toxicol Clin Toxicol 2003; 41:595.
- Mahr NC, Valdes A, Lamas G. Use of glucagon for acute intravenous diltiazem toxicity. Am J Cardiol 1997; 79:1570.
- Walter FG, Frye G, Mullen JT, et al. Amelioration of nifedipine poisoning associated with glucagon therapy. Ann Emerg Med 1993; 22:1234.
- Doyon S, Roberts JR. The use of glucagon in a case of calcium channel blocker overdose. Ann Emerg Med 1993; 22:1229.
- Levine M, Curry SC, Padilla-Jones A, Ruha AM. Critical care management of verapamil and diltiazem overdose with a focus on vasopressors: a 25-year experience at a single center. Ann Emerg Med 2013; 62:252.
- Kline JA, Tomaszewski CA, Schroeder JD, Raymond RM. Insulin is a superior antidote for cardiovascular toxicity induced by verapamil in the anesthetized canine. J Pharmacol Exp Ther 1993; 267:744.
- Boyer EW, Shannon M. Treatment of calcium-channel-blocker intoxication with insulin infusion. N Engl J Med 2001; 344:1721.
- Greene SL, Gawarammana I, Wood DM, et al. Relative safety of hyperinsulinaemia/euglycaemia therapy in the management of calcium channel blocker overdose: a prospective observational study. Intensive Care Med 2007; 33:2019.
- Patel NP, Pugh ME, Goldberg S, Eiger G. Hyperinsulinemic euglycemia therapy for verapamil poisoning: a review. Am J Crit Care 2007; 16:498.
- Kline JA, Leonova E, Raymond RM. Beneficial myocardial metabolic effects of insulin during verapamil toxicity in the anesthetized canine. Crit Care Med 1995; 23:1251.
- Kline JA, Raymond RM, Schroeder JD, Watts JA. The diabetogenic effects of acute verapamil poisoning. Toxicol Appl Pharmacol 1997; 145:357.
- Bechtel LK, Haverstick DM, Holstege CP. Verapamil toxicity dysregulates the phosphatidylinositol 3-kinase pathway. Acad Emerg Med 2008; 15:368.
- Jamaty C, Bailey B, Larocque A, et al. Lipid emulsions in the treatment of acute poisoning: a systematic review of human and animal studies. Clin Toxicol (Phila) 2010; 48:1.
- Levine M, Hoffman RS, Lavergne V, et al. Systematic review of the effect of intravenous lipid emulsion therapy for non-local anesthetics toxicity. Clin Toxicol (Phila) 2016; 54:194.
- Young AC, Velez LI, Kleinschmidt KC. Intravenous fat emulsion therapy for intentional sustained-release verapamil overdose. Resuscitation 2009; 80:591.
- Sirianni AJ, Osterhoudt KC, Calello DP, et al. Use of lipid emulsion in the resuscitation of a patient with prolonged cardiovascular collapse after overdose of bupropion and lamotrigine. Ann Emerg Med 2008; 51:412.
- Doepker B, Healy W, Cortez E, Adkins EJ. High-dose insulin and intravenous lipid emulsion therapy for cardiogenic shock induced by intentional calcium-channel blocker and Beta-blocker overdose: a case series. J Emerg Med 2014; 46:486.
- Bologa C, Lionte C, Coman A, Sorodoc L. Lipid emulsion therapy in cardiodepressive syndrome after diltiazem overdose--case report. Am J Emerg Med 2013; 31:1154.e3.
- Gueret G, Pennec JP, Arvieux CC. Hemodynamic effects of intralipid after verapamil intoxication may be due to a direct effect of fatty acids on myocardial calcium channels. Acad Emerg Med 2007; 14:761.
- Grunbaum AM, Gilfix BM, Gosselin S, Blank DW. Analytical interferences resulting from intravenous lipid emulsion. Clin Toxicol (Phila) 2012; 50:812.
- Grunbaum AM, Gilfix BM, Hoffman RS, et al. Review of the effect of intravenous lipid emulsion on laboratory analyses. Clin Toxicol (Phila) 2016; 54:92.
- Wolf LR, Spadafora MP, Otten EJ. Use of amrinone and glucagon in a case of calcium channel blocker overdose. Ann Emerg Med 1993; 22:1225.
- Varpula T, Rapola J, Sallisalmi M, Kurola J. Treatment of serious calcium channel blocker overdose with levosimendan, a calcium sensitizer. Anesth Analg 2009; 108:790.
- Kurola J, Leppikangas H, Magga J, et al. Effect of levosimendan in experimental verapamil-induced myocardial depression. Scand J Trauma Resusc Emerg Med 2010; 18:12.
- Abraham MK, Scott SB, Meltzer A, Barrueto F Jr. Levosimendan does not improve survival time in a rat model of verapamil toxicity. J Med Toxicol 2009; 5:3.
- Osthoff M, Bernsmeier C, Marsch SC, Hunziker PR. Levosimendan as treatment option in severe verapamil intoxication: a case report and review of the literature. Case Rep Med 2010; 2010.
- Graudins A, Wong KK. Comparative hemodynamic effects of levosimendan alone and in conjunction with 4-aminopyridine or calcium chloride in a rodent model of severe verapamil poisoning. J Med Toxicol 2010; 6:85.
- Salhanick SD, Shannon MW. Management of calcium channel antagonist overdose. Drug Saf 2003; 26:65.
- Frierson J, Bailly D, Shultz T, et al. Refractory cardiogenic shock and complete heart block after unsuspected verapamil-SR and atenolol overdose. Clin Cardiol 1991; 14:933.
- Holzer M, Sterz F, Schoerkhuber W, et al. Successful resuscitation of a verapamil-intoxicated patient with percutaneous cardiopulmonary bypass. Crit Care Med 1999; 27:2818.
- Durward A, Guerguerian AM, Lefebvre M, Shemie SD. Massive diltiazem overdose treated with extracorporeal membrane oxygenation. Pediatr Crit Care Med 2003; 4:372.
- Babatasi G, Massetti M, Verrier V, et al. [Severe intoxication with cardiotoxic drugs: value of emergency percutaneous cardiocirculatory assistance]. Arch Mal Coeur Vaiss 2001; 94:1386.
- Hendren WG, Schieber RS, Garrettson LK. Extracorporeal bypass for the treatment of verapamil poisoning. Ann Emerg Med 1989; 18:984.
- CLINICAL FEATURES
- Physical examination
- DIAGNOSTIC EVALUATION
- Initial resuscitation
- Approach to the selection of specific therapies
- - Severely symptomatic patients
- - Mildly symptomatic patients
- - Asymptomatic patients
- Gastrointestinal decontamination
- Specific therapies
- - Atropine
- - Intravenous calcium
- - Glucagon
- - Vasopressors
- - Insulin and glucose
- - Lipid emulsion therapy
- - Phosphodiesterase inhibitors
- - Other proposed treatments
- - Invasive treatment measures
- - Extracorporeal removal
- ADDITIONAL RESOURCES
- SUMMARY AND RECOMMENDATIONS