Digitalis (cardiac glycoside) poisoning
- Michael Levine, MD
Michael Levine, MD
- Assistant Professor of Emergency Medicine
- Department of Emergency Medicine, section of Medical Toxicology
- University of Southern California
- Ayrn O'Connor, MD
Ayrn O'Connor, MD
- Clinical Associate Professor of Emergency Medicine
- University of Arizona College of Medicine
- Section Editors
- Stephen J Traub, MD
Stephen J Traub, MD
- Section Editor — Toxicology
- Associate Professor of Emergency Medicine
- Mayo Medical School
- Michele M Burns, MD, MPH
Michele M Burns, MD, MPH
- Section Editor — Pediatric Toxicology
- Assistant Professor of Pediatrics
- Harvard Medical School
In 1785, Sir William Withering described the use of the foxglove plant, Digitalis purpurea, for treatment of heart failure . More than 200 years later, cardiac glycosides are still prescribed for patients with atrial fibrillation and heart failure or left ventricular dysfunction.
While the overall use of digitalis has declined, the number of patients admitted with digitalis toxicity has remained stable and the use of digitalis antibody fragments has increased . In 2011, there were 2513 cases of cardiac glycoside exposures reported to United States poison control centers. Of these, 132 patients suffered major toxicity and 27 died .
In addition to digitalis, other cardiac glycosides exist and have been associated with toxicity. These include: the xenobiotics ouabain and lanatoside C; various plants, including foxglove, dogbane, red squill, lily of the valley, oleander, and henbane; and bufadienolides, cardioactive steroids found in the skin of toads belonging to the Bufonidae family . In 2011, there were an additional 1376 cases of cardiac glycoside exposure from various plant species .
The pharmacology, diagnosis, and management of acute and chronic digitalis poisoning will be reviewed here. The dosing of digoxin-specific antibody (Fab) fragments for the treatment of digoxin toxicity and the therapeutic use of digoxin are discussed separately. (See "Dosing regimen for digoxin-specific antibody (Fab) fragments in patients with digoxin toxicity" and "Use of digoxin in heart failure due to systolic dysfunction" and "Control of ventricular rate in atrial fibrillation: Pharmacologic therapy", section on 'Digoxin' and "Treatment with digoxin: Initial dosing, monitoring, and dose modification".)
PHARMACOLOGY AND CELLULAR TOXICOLOGY
Cardiac glycosides all possess a steroid nucleus with an unsaturated lactone at the C17 position, and at least one glycosidic residue at the C3 position (figure 1) . Cardiac glycosides are used primarily to increase inotropy in cardiac myocytes but also affect cells in the vascular smooth muscle and sympathetic nervous system [5-7].
- Eichhorn EJ, Gheorghiade M. Digoxin. Prog Cardiovasc Dis 2002; 44:251.
- Hussain Z, Swindle J, Hauptman PJ. Digoxin use and digoxin toxicity in the post-DIG trial era. J Card Fail 2006; 12:343.
- Bronstein AC, Spyker DA, Cantilena LR Jr, et al. 2011 Annual report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 29th Annual Report. Clin Toxicol (Phila) 2012; 50:911.
- Brubacher JR, Lachmanen D, Ravikumar PR, Hoffman RS. Efficacy of digoxin specific Fab fragments (Digibind) in the treatment of toad venom poisoning. Toxicon 1999; 37:931.
- Rocco TP, Fang JC. Pharmacotherapy of congestive heart failure. In: Goodman & Gilman's The Pharmocological Basis of Therapeutics, 11th, Brunton LL, Lazo JS, Parker KL. (Eds), McGraw-Hill, New York 2006. p.869.
- Smith TW. Digitalis. Mechanisms of action and clinical use. N Engl J Med 1988; 318:358.
- Newton GE, Tong JH, Schofield AM, et al. Digoxin reduces cardiac sympathetic activity in severe congestive heart failure. J Am Coll Cardiol 1996; 28:155.
- Matthews CG. Cellular Physiology of Nerve and Muscle, 3rd, Blackwell Science, Malden 1998.
- Li-Saw-Hee FL, Lip GY. Digoxin revisited. QJM 1998; 91:259.
- Demiryürek AT, Demiryürek S. Cardiotoxicity of digitalis glycosides: roles of autonomic pathways, autacoids and ion channels. Auton Autacoid Pharmacol 2005; 25:35.
- Ma G, Brady WJ, Pollack M, Chan TC. Electrocardiographic manifestations: digitalis toxicity. J Emerg Med 2001; 20:145.
- Ribner HS, Plucinski DA, Hsieh AM, et al. Acute effects of digoxin on total systemic vascular resistance in congestive heart failure due to dilated cardiomyopathy: a hemodynamic-hormonal study. Am J Cardiol 1985; 56:896.
- Hauptman PJ, Kelly RA. Digitalis. Circulation 1999; 99:1265.
- Tisdale JE, Gheorghiade M. Acute hemodynamic effects of digoxin alone or in combination with other vasoactive agents in patients with congestive heart failure. Am J Cardiol 1992; 69:34G.
- Lip GY, Metcalfe MJ, Dunn FG. Diagnosis and treatment of digoxin toxicity. Postgrad Med J 1993; 69:337.
- Greiner B, Eichelbaum M, Fritz P, et al. The role of intestinal P-glycoprotein in the interaction of digoxin and rifampin. J Clin Invest 1999; 104:147.
- Drescher S, Glaeser H, Mürdter T, et al. P-glycoprotein-mediated intestinal and biliary digoxin transport in humans. Clin Pharmacol Ther 2003; 73:223.
- Lin JH, Yamazaki M. Clinical relevance of P-glycoprotein in drug therapy. Drug Metab Rev 2003; 35:417.
- Katoh M, Nakajima M, Yamazaki H, Yokoi T. Inhibitory effects of CYP3A4 substrates and their metabolites on P-glycoprotein-mediated transport. Eur J Pharm Sci 2001; 12:505.
- Cauffield JS, Gums JG, Grauer K. The serum digoxin concentration: ten questions to ask. Am Fam Physician 1997; 56:495.
- Guglielminotti J, Tremey B, Maury E, et al. Fatal non-occlusive mesenteric infarction following digoxin intoxication. Intensive Care Med 2000; 26:829.
- Bhatia SJ. Digitalis toxicity--turning over a new leaf? West J Med 1986; 145:74.
- Bismuth C, Gaultier M, Conso F, Efthymiou ML. Hyperkalemia in acute digitalis poisoning: prognostic significance and therapeutic implications. Clin Toxicol 1973; 6:153.
- Eddleston M, Rajapakse S, Jayalath S, et al. Anti-digoxin Fab fragments in cardiotoxicity induced by ingestion of yellow oleander: a randomised controlled trial. Lancet 2000; 355:967.
- Eddleston M, Ariaratnam CA, Sjöström L, et al. Acute yellow oleander (Thevetia peruviana) poisoning: cardiac arrhythmias, electrolyte disturbances, and serum cardiac glycoside concentrations on presentation to hospital. Heart 2000; 83:301.
- Bayer MJ. Recognition and management of digitalis intoxication: implications for emergency medicine. Am J Emerg Med 1991; 9:29.
- Smith TW. New advances in the assessment and treatment of digitalis toxicity. J Clin Pharmacol 1985; 25:522.
- Sonnenblick M, Abraham AS, Meshulam Z, Eylath U. Correlation between manifestations of digoxin toxicity and serum digoxin, calcium, potassium, and magnesium concentrations and arterial pH. Br Med J (Clin Res Ed) 1983; 286:1089.
- Ujhelyi MR, Green PJ, Cummings DM, et al. Determination of free serum digoxin concentrations in digoxin toxic patients after administration of digoxin fab antibodies. Ther Drug Monit 1992; 14:147.
- Flanagan RJ, Jones AL. Fab antibody fragments: some applications in clinical toxicology. Drug Saf 2004; 27:1115.
- Dasgupta A. Endogenous and exogenous digoxin-like immunoreactive substances: impact on therapeutic drug monitoring of digoxin. Am J Clin Pathol 2002; 118:132.
- Kelly RA, Smith TW. Recognition and management of digitalis toxicity. Am J Cardiol 1992; 69:108G.
- Antman EM, Wenger TL, Butler VP Jr, et al. Treatment of 150 cases of life-threatening digitalis intoxication with digoxin-specific Fab antibody fragments. Final report of a multicenter study. Circulation 1990; 81:1744.
- DigiFab package insert. Savage Laboratories. Melville, NY 2004.
- Brubacher JR, Ravikumar PR, Bania T, et al. Treatment of toad venom poisoning with digoxin-specific Fab fragments. Chest 1996; 110:1282.
- Cheung K, Urech R, Taylor L, et al. Plant cardiac glycosides and digoxin Fab antibody. J Paediatr Child Health 1991; 27:312.
- Smith TW, Haber E, Yeatman L, Butler VP Jr. Reversal of advanced digoxin intoxication with Fab fragments of digoxin-specific antibodies. N Engl J Med 1976; 294:797.
- Woolf AD, Wenger T, Smith TW, Lovejoy FH Jr. The use of digoxin-specific Fab fragments for severe digitalis intoxication in children. N Engl J Med 1992; 326:1739.
- de Silva HA, Fonseka MM, Pathmeswaran A, et al. Multiple-dose activated charcoal for treatment of yellow oleander poisoning: a single-blind, randomised, placebo-controlled trial. Lancet 2003; 361:1935.
- Eddleston M, Juszczak E, Buckley NA, et al. Multiple-dose activated charcoal in acute self-poisoning: a randomised controlled trial. Lancet 2008; 371:579.
- Henderson RP, Solomon CP. Use of cholestyramine in the treatment of digoxin intoxication. Arch Intern Med 1988; 148:745.
- Rawashdeh NM, al-Hadidi HF, Irshaid YM, Battah AK. Gastrointestinal dialysis of digoxin using cholestyramine. Pharmacol Toxicol 1993; 72:245.
- Bower, JO, Mengle, HA. The additive effect of calcium and digitalis: a warning, with a report of two deaths. JAMA 1936; 106:1511.
- SHRAGER MW. Digitalis intoxication; a review and report of forty cases, with emphasis on etiology. AMA Arch Intern Med 1957; 100:881.
- Kne, T, Brokaw, M, Wax, P. Fatality from calcium chloride in a chronic digoxin toxic patient. J Toxicol Clin Toxicol 1997; 5:505.
- Gold, H, Edwards, DJ. The effects of aubain on the heart in the presence of hypercalcemia. Am Heart J 1927; 3:45.
- Nola GT, Pope S, Harrison DC. Assessment of the synergistic relationship between serum calcium and digitalis. Am Heart J 1970; 79:499.
- Hack JB, Woody JH, Lewis DE, et al. The effect of calcium chloride in treating hyperkalemia due to acute digoxin toxicity in a porcine model. J Toxicol Clin Toxicol 2004; 42:337.
- Fenton F, Smally AJ, Laut J. Hyperkalemia and digoxin toxicity in a patient with kidney failure. Ann Emerg Med 1996; 28:440.
- Van Deusen SK, Birkhahn RH, Gaeta TJ. Treatment of hyperkalemia in a patient with unrecognized digitalis toxicity. J Toxicol Clin Toxicol 2003; 41:373.
- Levine M, Nikkanen H, Pallin DJ. The effects of intravenous calcium in patients with digoxin toxicity. J Emerg Med 2011; 40:41.
- Renard C, Grene-Lerouge N, Beau N, et al. Pharmacokinetics of digoxin-specific Fab: effects of decreased renal function and age. Br J Clin Pharmacol 1997; 44:135.
- Ujhelyi MR, Robert S, Cummings DM, et al. Disposition of digoxin immune Fab in patients with kidney failure. Clin Pharmacol Ther 1993; 54:388.
- Ujhelyi MR, Robert S, Cummings DM, et al. Influence of digoxin immune Fab therapy and renal dysfunction on the disposition of total and free digoxin. Ann Intern Med 1993; 119:273.
- Warren SE, Fanestil DD. Digoxin overdose. Limitations of hemoperfusion-hemodialysis treatment. JAMA 1979; 242:2100.
- Slattery JT, Koup JR. Haemoperfusion in the management of digoxin toxicity: is it warranted? Clin Pharmacokinet 1979; 4:395.
- Mowry JB, Burdmann EA, Anseeuw K, et al. Extracorporeal treatment for digoxin poisoning: systematic review and recommendations from the EXTRIP Workgroup. Clin Toxicol (Phila) 2016; 54:103.
- Santos-Araújo C, Campos M, Gavina C, et al. Combined use of plasmapheresis and antidigoxin antibodies in a patient with severe digoxin intoxication and acute renal failure. Nephrol Dial Transplant 2007; 22:257.
- Rabetoy GM, Price CA, Findlay JW, Sailstad JM. Treatment of digoxin intoxication in a renal failure patient with digoxin-specific antibody fragments and plasmapheresis. Am J Nephrol 1990; 10:518.
- Gittelman MA, Stephan M, Perry H. Acute pediatric digoxin ingestion. Pediatr Emerg Care 1999; 15:359.
- Thacker D, Sharma J. Digoxin toxicity. Clin Pediatr (Phila) 2007; 46:276.
- PHARMACOLOGY AND CELLULAR TOXICOLOGY
- CLINICAL FEATURES AND DIAGNOSIS
- Physical examination
- Clinical manifestations
- LABORATORY AND ECG EVALUATION
- Approach to testing
- Electrolyte abnormalities
- Serum digoxin concentration
- DIFFERENTIAL DIAGNOSIS
- Basic measures and arrhythmias
- Antidotal therapy with antibody (Fab) fragments
- - Indications and general approach
- - Patients with pacemakers
- GI decontamination
- Electrolyte abnormalities
- Renal failure
- - General care
- - Fab fragment dosing
- - Extracorporeal removal
- PEDIATRIC CONSIDERATIONS
- ADDITIONAL RESOURCES
- SUMMARY AND RECOMMENDATIONS