Digitalis Intoxication
Tóm tắt
Digitalis continues to be a commonly prescribed cardiac agent for the treatment of congestive heart failure and atrial fibrillation. The incidence of severe digitalis poisonings and adverse effects may be decreasing for a variety of reasons, but the narrow therapeutic: toxic ratio of digitalis makes toxicity a continuing problem. The advent of immunotherapy using digoxin-specific antibody (ovine) fragments (digoxin immune Fab; Fab) within the past 10 years has radically changed the management of severe digitalis poisoning in both children and adults. Several large clinical trials involving cumulatively more than 1000 patients have established the efficacy of digoxin immune Fab in resolving the signs of digitalis toxicity. Often improvements in dysrhythmias, hyperkalaemia, gastrointestinal complaints and/or neurological symptoms are noted within 30 minutes of infusion, with complete reversal of toxicity in 2 to 4 hours in 85 to 90% of patients. In many instances, those patients having only partial responses are probably undertreated through a miscalculated total body burden of digoxin or digitoxin. Administration of digoxin immune Fab has been remarkably free of associated adverse effects: allergic reactions (mostly rashes) occur in <1% of recipients. Recurrence of congestive failure due to digitalis withdrawal has been noted in about 1 to 3% of patients who received Fab. Recurrence of atrial fibrillation with a rapid ventricular response has also been seen. Recrudescence of digitalis toxicity occurs in about 3% of Fab recipients, usually within 3 days of the initial Fab dose and often related to undertreatment due to a miscalculation of the Fab needed to counter a total body burden of digitalis. Hypokalaemia has been noted in up to 4% of Fab recipients. For these reasons, it is recommended that the patient’s medical status be closely watched after administration of digoxin immune Fab, with cardiac monitoring for several days and frequent measurements of serum potassium. Newer laboratory techniques such as ultrafiltration of the sample prior to analysis by immunoassay will improve the clinician’s ability to monitor free serum digoxin concentrations after Fab administration. In this way the clinician can detect late-occurring increases in free digoxin concentrations that might herald recrudescing toxicity and necessitate repeated treatment with Fab. Indications for use of digoxin immune Fab have been interpreted broadly by clinicians as the antidote has become more widely available. However, most clinicians continue to reserve Fab for those patients who are confirmed, by a reliable history of overdosage and/or an elevated post-distribution serum digitalis concentration, to be experiencing the toxic effects of digitalis and who have life-threatening symptoms and signs. These include cardiac arrhythmias and/or conduction blocks that are haemodynamically compromising, and/or rising levels of potassium in the blood. Clinicians are well advised to base their decision to use Fab in the context of the individual patient’s risks for a poor prognosis, such as: (a) advanced age; (b) history of a massive overdose with early signs of rapidly progressing toxicity; (c) the presence of advanced atrioventricular block and arrhythmias; (d) persistent hyperkalaemia; and (e) pre-existing cardiac conditions or congenital heart disease. Digoxin immune Fab has also been used with good results in infants and children, in patients with renal failure, and in patients experiencing the effects of other glycosides such as digitoxin or lanatoside C, or advanced toxicity from plant-derived cardiac glycosides. Because of the longer serum half-lives and persistence of other glycosides such as digitoxin, and because of the inefficiency of clearance of digoxin in patients with renal failure, longer monitoring for signs of recrudescing toxicity is recommended in such patients after Fab administration.
Tài liệu tham khảo
Smith TW. Digitalis — mechanisms of action and clinical use. N Engl J Med 1988; 318: 358–65
Beller GA, Smith TW, Abelmann WH, et al. Digitalis intoxication: a prospective clinical study with serum level correlations. N Engl J Med 1971; 284: 989–97
Henry DA, Lawson DA, Lowe JM, et al. The changing pattern of toxicity to digoxin. Postgrad Med J 1981; 57: 358–62
Dally S, Alperovitch A, Lagier G, et al. Facteurs prognostiques de l’intoxication digitalique aigue. Nouv Presse Med 1981; 10: 2257–60
Taboulet P, Baud FJ, Bismuth C. Clinical features and management of digitalis poisoning — rationale for immunotherapy. Clin Toxicol 1993; 31: 247–60
Kelley RA, Smith TW. Recognition and management of digitalis toxicity. Am J Cardiol 1992; 69: 108G–119G
Mahdyoon H, Battilana G, Rosman H, et al. The evolving pattern of digoxin intoxication: observations at a large urban hospital from 1980–1988. Am Heart J 1990; 120: 1189–94
Kernan WN, Castellsague J, Perlman GD, et al. Incidence of hospitalization for digitalis toxicity among elderly Americans. Am J Med 1994; 96: 426–31
Litovitz TL, Clark LR, Soloway RA. 1993 Annual report of the American Association of Poison Control Centers toxic exposure surveillance system. Am J Emerg Med 1994; 12: 546–84
Lansteiner K. The specificity of serological reactions. Massachusetts: Harvard University Press, 1945: 181
Card J, Smith TW, Jaton JC, et al. The isolation of digoxin-specific antibody and its use in reversing the effects of digoxin. Proc Natl Acad Sci USA 1971; 68: 2401–6
Butler VP, Chen JP. Digoxin-specific antibodies. Proc Natl Acad Sci USA 1967; 57: 71–8
Watson JF, Butler VP. Biologic activity of digoxin specific antisera. Clin Res 1968; 16: 252
Schmidt DH, Butler VP. Immunologic protection against digitalis toxicity [abstract]. Circulation 1968; 38 Suppl. 6: 174
Schmidt DH, Butler VP. Reversal of digoxin toxicity with specific antibodies. J Clin Invest 1971; 50: 1738–44
Butler VP. Digoxin: immunologic approaches to measurement and reversal of toxicity. N Engl J Med 1970; 283: 1150–6
Butler VP, Smith TW, Schmidt DH, et al. Immunological reversal of the effects of digoxin. Fed Proc 1977; 36: 2235–41
Smith TW, Butler VP, Haber E. Characterization of antibodies of high affinity and specificity for the digitalis glycoside digoxin. Biochemistry 1970; 9: 331–7
Curd J, Smith TW, Jaton J, et al. The isolation of digoxin-specific antibody and its use in reversing the effects of digoxin. Proc Natl Acad Sci USA 1971; 68: 2401–6
Hougen TJ, Lloyd BL, Smith TW. Effects of inotropic and arrhythmogenic digoxin doses and of digoxin-specific antibody on myocardial monovalent cation transport in the dog. Circ Res 1979; 44: 23–31
Hess T, Scholtysik G, Riesen W. The prevention and reversal of digoxin intoxication with specific antibodies. Am Heart J 1978; 96: 486–95
Zalcberg JR. Monoclonal antibodies to drugs: novel diagnostic and therapeutic reagents. Pharmacol Ther 1985; 28: 273–85
Lechat P, Mudgett-Hunter M, Margolies MN, et al. Reversal of lethal digoxin toxicity in guinea pigs using monoclonal antibodies and Fab fragments. J Pharmacol Exp Ther 1984; 229: 210–3
Smith TW, Haber E, Yeatman L, et al. Reversal of advanced digoxin intoxication with Fab fragments of digoxin-specific antibodies. N Engl J Med 1976; 294: 797–800
Smith TW, Butler VP, Haber E, et al. Treatment of life-threatening digitalis intoxication with digoxin-specific Fab antibody fragments. N Engl J Med 1982; 307: 1357–62
Smith TW. Review of clinical experience with digoxin immune Fab (ovine). Am J Emerg Med 1991; 9 Suppl. 1: 1–6
Schaumann W, Kaufmann B, Neubert P, et al. Kinetics of the Fab fragments of digoxin antibodies and of bound digoxin in patients with severe digoxin intoxication. Eur J Clin Pharmacol 1986; 30: 527–33
Antman EM, Wenger TL, Butler VP, et al. Treatment of 150 cases of life-threatening digitalis intoxication with digoxin-specific Fab antibody fragments. Circulation 1990; 81: 1744–52
Smolarz A, Roesch E, Lenz E, et al. Digoxin-specific antibody (Fab) fragments in 34 cases of severe digitalis intoxication. J Toxicol Clin Toxicol 1985; 23: 327–40
Taboulet P, Baud FJ, Bismuth C, et al. Acute digitalis intoxication — is pacing still appropriate? Clin Toxicol 1993; 31: 61–73
Hickey AR, Wenger TL, Carpenter VP, et al. Digoxin immune Fab therapy in the management of digitalis intoxication: safety and efficacy results of an observational surveillance study. J Am Coll Cardiol 1991; 17: 590–8
Wenger TL, Butler VP, Haber E, et al. Treatment of 63 severely digitalis-toxic patients with digoxin specific antibody fragments. J Am Coll Cardiol 1985; 5: 118A
Woolf AD, Wenger T, Smith TW, et al. The use of digoxin-specific Fab fragments for severe digitalis intoxication in children. N Engl J Med 1992; 326: 1739–44
Woolf AD, Wenger TL, Smith TW, et al. Results of multicenter studies of digoxin-specific antibody fragments in managing digitalis intoxication in the pediatric population. Am J Emerg Med 1991; 9 Suppl. 1: 16–20
Marchlinski FE, Hook BG, Callans DJ. Which cardiac disturbances should be treated with digoxin immune Fab (ovine) antibody? Am J Emerg Med 1991; 9 Suppl. 1: 24–8
Desantola JR, Marchlinski FE. Response of digoxin toxic atrial tachycardia to digoxin-specific Fab fragments. Am J Cardiol 1986; 58: 1109–10
Wofford JL, Ettinger WH. Risk factors and manifestations of digoxin toxicity in the elderly. Am J Emerg Med 1991; 9 Suppl. 1: 11–5
Wells TG, Young RA, Kearns GL. Age-related differences in digoxin toxicity and its treatment. Drug Saf 1992; 7: 135–51
Hastreiter AR, van der Horst RL, Chow-Tung E. Digitalis toxicity in infants and children. Pediatr Cardiol 1984; 5: 131–48
Graves SW, Valdes R, Brown DA, et al. Endogenous digoxin-immunoreactive substance in human pregnancies. Clin Endocrinol Metab 1984; 58: 740–51
Graves SW, Brown B, Valdes R. An endogenous digoxin-like substance in patients with renal impairment. Ann Intern Med 1983; 99: 604–8
Nanji AA, Greenway DC. Falsely raised plasma digoxin concentrations in liver disease. BMJ 1985; 290: 432–3
Wolach B, Carmi D, Shilo L, et al. Endogenous digoxin-like factor in neonates: effect of age and relation to serum bilirubin levels. Acta Pediatr Scand 1989; 78: 364–8
Valdes R, Graves SW, Brown BA, et al. Endogenous substance in newborn infants causing false positive digoxin measurements. J Pediatr 1983; 102: 947–50
Yatscoff RW, Desjardins PRE, Dalton JG. Digoxin-like immunoreactivity in the serum of neonates and uremic patients as measured in the Abbott TDX. Clin Chem 1984; 30: 588
Bayer MJ. Recognition and management of digitalis intoxication: implications for emergency medicine. Am J Emerg Med 1991; 9 Suppl. 1: 29–32
Woolf AD. Revising the management of digitalis poisoning. Clin Toxicol 1993; 31: 275–6
Hess T, Stucki P, Barandum S, et al. Treatment of a case of lanatoside C intoxication with digoxin-specific F(ab′)2 antibody fragments. Am Heart J 1979; 98: 767–71
Sabouraud A, Urtizberea M, Cano N, et al. Specific anti-digoxin Fab fragments: an available antidote for proscillaridin and scilliroside poisoning? Hum Exp Toxicol 1990; 9: 191–3
Ochs H, Smith TW. Reversal of advanced digitoxin toxicity and modification of pharmacokinetics by specific antibodies and Fab fragments. J Clin Invest 1977; 60: 1303–13
Hess T, Scholtysik G, Riesen W. The effectiveness of digoxin-specific F(ab′)2-antibody fragments in the treatment of digitoxin poisoning: experimental investigations in the cat. Eur J Clin Invest 1980; 10: 93–7
Domart Y, Bismuth C, Schermann JM, et al. Intoxication par la digitoxine: reversibilite d’une fibrillation ventriculaire par fragments Fab d’anticorps antidigoxine. Nouv Presse Med 1982; 11: 3827–30
Baud F, Bismuth C, Pontal PG, et al. Time course of anti-digoxin Fab fragment and plasma digitoxin concentrations in an acute digitalis intoxication. J Toxicol Clin Toxicol 1982; 19: 857–60
Hess T, Riesen W, Scholtysik G, et al. Digitoxin intoxication with severe thrombocytopenia: reversal by digoxin-specific antibodies. Eur J Clin Invest 1983; 13: 159–63
Lignian H, Vincent JL, Hallemans R. Treatment of severe digitoxin intoxication by digoxin-specific Fab antibody fragments. Acta Cardiol 1984; 39: 301–5
Autret E, Chantepie A, Bloc D, et al. Utilisation des anticorps anti-digoxine au cours d’une intoxication digitalique chez un nourrisson. Arch Fr Pediatr 1985; 42: 803–4
Schmitt K, Tulzer G, Hackel F, et al. Massive digitoxin intoxication treated with digoxin-specific antibodies in a child. Pediatr Cardiol 1994; 15: 48–9
Aeberhard P, Butler VP, Smith TW, et al. Le traitement d’une intoxication digitalique massive (20 mg de digitoxine) par les anticorps anti-digoxine fractionnes (Fab). Arch Mal Coeur Vaiss 1980; 12: 1471–8
Radford DJ, Gillies AD, Hinds JA, et al. Naturally occurring cardiac glycosides. Med J Aust 1986; 144: 540–4
Saravanapavananthan N, Ganeshamoorthy J. Yellow oleander poisoning — a study of 170 cases. Forens Sci Int 1988; 36: 247–50
Kaojarern S, Sukhupunyarak S, Mokkhavesa C. Oleander Yee Tho poisoning. J Med Assoc Thai 1986; 69: 108–11
Clark RF, Seiden BS, Curry SC. Digoxin-specific Fab fragments in the treatment of oleander toxicity in a canine model. Ann Emerg Med 1991; 20: 1073–7
Dickstein ES, Kunkel FW. Foxglove tea poisoning. Am J Med 1980; 69: 167–9
Rich SA, Libera JM, Locke RJ. Treatment of foxglove extract poisoning with digoxin-specific Fab fragments. Ann Emerg Med 1993; 22: 1904–7
Bain RJI. Accidental digitalis poisoning due to drinking herbal tea. BMJ 1985; 290: 1624
Brewster D. Herbal poisoning: a case report of a fatal yellow oleander poisoning from the Solomon Islands. Ann Trop Paediatr 1986; 6: 289–91
Osterloh J, Herold S, Pond S. Oleander interference in the digoxin radioimmunoassay in a fatal ingestion. JAMA 1982; 247: 1596–7
Haynes BE, Bessen HA, Wightman WD. Oleander tea: herbal draught of death. Ann Emerg Med 1985; 14: 350–3
Cheung K, Hinds JA, Duffy P. Detection of poisoning by plant-origin cardiac glycoside with the Abbott TDx analyzer. Clin Chem 1989; 35: 295–7
Shumaik GM, Wu AW, Ping AC. Oleander poisoning: treatment with digoxin-specific Fab antibody fragments. Ann Emerg Med 1988; 17: 732–5
Sinclair AJ, Hewick DS, Johnston PC, et al. Kinetics of digoxin and anti-digoxin antibody fragments during treatment of digoxin toxicity. Br J Clin Pharmacol 1989; 28: 352–6
Argyle JC. Effect of digoxin antibodies on TDx digoxin assay. Clin Chem 1986; 32: 1616–7
Gibb I, Adams PC, Parnham AJ, et al. Plasma digoxin: assay anomalies in Fab-treated patients. Br J Clin Pharmacol 1983; 16: 445–7
Hursting MJ, Raisys VA, Opheim KE, et al. Determination of free digoxin concentrations in serum for monitoring Fab treatment for digoxin overdose. Clin Chem 1987; 33: 1652–5
Lemon M, Andrews DJ, Binks AM, et al. Concentrations of free serum digoxin after treatment with antibody fragments. BMJ 1987; 295: 1520–1
Banner W, Bach P, Burk B, et al. Influence of assay methods on serum concentrations of digoxin during Fab fragment treatment. Clin Toxicol 1992; 30: 259–67
Ujhelyi MR, Green PJ, Cummings DM, et al. Determination of free digoxin concentrations in digoxin toxic patients after administration of digoxin Fab antibodies. Ther Drug Monit 1992; 14: 147–54
Ujhelyi MR, Colucci RD, Cummings DM, et al. Monitoring serum digoxin concentrations during digoxin immune Fab therapy. DICP Ann Pharmacother 1991; 25: 1047–9
Nuwayhid NF, Johnson GF. Digoxin elimination in a functionally anephric patient after digoxin-specific Fab fragment therapy. Ther Drug Monit 1989; 2: 680–5
Kirkpatrick CH. Allergic histories and reactions of patients treated with digoxin immune Fab (ovine) antibody. Am J Emerg Med 1991; 9 Suppl. 1: 7–10
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: 273–7
Lewander WJ, Gaudreault P, Einhorn A, et al. Acute pediatric digoxin ingestion — a ten year experience. Am J Dis Child 1986; 140: 770–3
Murphy DJ, Bremner WF, Haber E, et al. Massive digoxin poisoning treated with Fab fragments of digoxin-specific antibodies. Pediatrics 1982; 70: 432–3
Zucker AR, Lacina SJ, DasGupta DS, et al. Fab fragments of digoxin-specific antibodies used to reverse ventricular fibrillation induced by digoxin ingestion in a child. Pediatrics 1982; 70: 468–71
Rossi R, Leititis JU, Hagel KJ, et al. Severe digoxin intoxication in a child treated by infusion of digoxin-specific Fab-antibody fragments. Eur J Pediatr 1984; 142: 138–40
Hussain MI, Murray R, Williams BP. Purified digoxin specific Fab fragments. Indiana Med 1985; 780: 781
Presti S, Friedman D, Saslow J, et al. Digoxin toxicity in a premature infant: treatment with Fab fragments of digoxin-bound antibodies. Pediatr Cardiol 1985; 6: 91–3
Kearns GL, Moss M, Clayton BD, et al. Pharmacokinetics and efficacy of digoxin specific Fab fragments in a child following massive digoxin overdose. J Clin Pharmacol 1989; 29: 901–8
Nollet H, Verhaaren H, Stroobandt R, et al. Delayed elimination of digoxin antidotum determined by radioimmunoassay. J Clin Pharmacol 1989; 29: 41–5
Kaufman J, Leikin J, Kendzierski D, et al. Use of digoxin Fab immune fragments in a seven-day-old infant. Pediatr Emerg Care 1990; 6: 118–21
Rose SR, Gorman RL, McDaniel J. Fatal digoxin poisoning: an unsuccessful resuscitation with use of digoxin-immune Fab. Am J Emerg Med 1987; 5: 509–11
Wenger TL. Experience with digoxin immune Fab (ovine) in patients with renal impairment. Am J Emerg Med 1991; 9 Suppl. 1: 21–3
Erdmann E, Mair W, Knedel M, et al. Digitalis intoxication and treatment with digoxin antibody fragments in renal failure. Klin Wochenschr 1989; 67: 16–9
Allen NM, Dunham GD, Sailstad JM, et al. Clinical and pharmacokinetic profiles of digoxin immune Fab in four patients with renal impairment. DICP Ann Pharmacol 1991; 25: 1315–20
Ujhelyi MR, Robert S, Cummings DM, et al. Disposition of digoxin immune Fab in patients with kidney failure. Clin Pharmacol Ther 1993; 54: 388–94
Withering W. An account of the foxglove, and some of its medical uses: with practical remarks on dropsy, and other diseases. In: Willius FA, Keys TE, editors. Classics of cardiology. New York: Henry Schuman, Inc., 1961: 231–52