Diagnosis and Treatment of Digoxin Toxicity

Home , Cardiac glycoside, Digoxin, Digoxin toxicity

Postgrad Med J: first published as 10.1136/pgmj.69.811.337 on 1 May 1993. Downloaded from Postgrad Med J (1993) 69, 337 - 339 i) The Fellowship of Postgraduate Medicine, 1993

Review Article Diagnosis and treatment ofdigoxin toxicity Gregory Y.H. Lip, Malcolm J. Metcalfe and Francis G. Dunn Department ofCardiology, Stobhill General Hospital, Glasgow G21 3UW, UK

Introduction Cardiac glycosides are unusual in having a narrow important to emphasize that the clinical diagnosis therapeutic range, which is idiosyncratic to the of toxicity is of fundamental importance and individual. In view of this it is perhaps not surpris- should not be discarded because of 'normal' ing that toxicity is a common occurrence, being plasma digoxin concentrations. reported in up to 35% of digitalized patients.' There are several mechanisms which can lead to Use ofplasma concentration measurements this problem. Firstly, digoxin is excreted mainly by the kidneys, and therefore, any impairment ofrenal In an attempt to improve digoxin therapy, it is function may lead to higher than expected plasma frequently advocated that the plasma digoxin con- concentrations. Congestive cardiac failure, renal centration should be measured. Trough plasma failure and advanced age can also cause toxicity by concentrations below 0.8 ng/ml (1.0 nmol/l) are reducing the volume of distribution of the drug. considered sub-therapeutic and levels greater than Concomitant electrolyte imbalance, notably 2.0 ng/ml (2.56 nmol/l) toxic. Unfortunately, there hypokalaemia, hypomagnesaemia and hypercal- is a marked overlap of measured plasma levels copyright. caemia can potentiate digoxin toxicity. Approx- between groups of patients with and without imately 30% of digoxin is plasma protein bound evidence of toxicity.3'4 For example, one patient and thus certain other drugs such as amiodarone may exhibit evidence of toxicity at a measured and calcium antagonists can lead to higher than plasma drug level ofonly 0.8 ng/ml, whilst another expected plasma concentrations. Lastly, several may be symptom free at a level of 3.0 ng/ml. clinical conditions such as hypothyroidism, It can thus be seen that plasma level concentra- chronic lung disease and cardiac amyloid are tion estimation is only of limited clinical value. associated with an abnormally high myocardial Plasma level measurements may be useful to http://pmj.bmj.com/ sensitivity to digoxin. Despite all of this, however, confirm clinical signs of toxicity or to see whether there is often still no clear relationship between or not there is any scope for reducing the dose and these factors and manifest toxicity. still achieving a therapeutic effect. Plasma levels are also useful to monitor compliance, to allow adjust- ment of dosage in the presence of certain con- Diagnosis oftoxicity comitant therapy and (in certain circumstances) to

monitor treatment of overdosage. There is, never- on September 24, 2021 by guest. Protected Clinicalfeatures theless, no place for performing 'routine' drug level assessments in clinical practice. Features of cardiac glycoside toxicity are usually non-specific and can be conveniently divided into cardiac and non-cardiac effects.2'3 Non-cardiac General principles ofmanagement symptoms such as anorexia, nausea, vomiting, lethargy, headaches, confusion and more rarely When a patient is diagnosed as suffering from visual disturbances are the most frequent present- digoxin toxicity, the initial step is to assess the ing features. With increasing toxicity, the more severity of the problems. The reason for the serious cardiac features become inevitable, development of toxicity should always be although occasionally they can be the presenting thoroughly sought: for example, use of an inap- problem. Almost any permutation of heart block, propriate high dose, the addition of concomitant brady- and tachydysrhythmias are possible.2 It is medication or the development of a reduced volume of distribution arising owing, for example, to progression of heart failure or development of Correspondence: G.Y.H. Lip, M.R.C.P. renal impairment. The question ofeither accidental Accepted: 4 December 1992 or deliberate overdosage should also be considered. 338 G.Y.H. LIP et al. Postgrad Med J: first published as 10.1136/pgmj.69.811.337 on 1 May 1993. Downloaded from

If the evidence of toxicity is relatively minor Specific aspects ofmanagement with, for example, symptoms of nausea, withdrawal of the drug is often the only specific Activated charcoal treatment required. More serious evidence of toxicity, particularly with cardiac involvement, One of the most effective agents for the treatment requires admission to hospital. ofdigoxin toxicity is activated charcoal. This agent If there is no evidence of serious cardiac prob- is especially useful for patients who have taken a lems, such as heart block or significant dysrhyth- recent overdosage of digoxin, for patients without mias, then following the withdrawal of the drug serious evidence of toxicity but otherwise sympto- and the correction of electrolyte imbalance, symp- matic, or in situations of serious toxicity when tomatic measures will usually suffice. The presence digoxin-specific antibodies are unavailable. In of major dysrhythmias is clearly potentially life- order to achieve an adequate therapeutic response, threatening and carries a high mortality. In these multiple oral doses of activated charcoal are often circumstances, a rapid and more aggressive man- required to maintain an effective concentration agement stratagem must therefore be followed, gradient. A suggested regimen is a loading dose of ideally within the coronary care unit with 50-100 g, followed by either 10 g hourly, 10-20 g experienced staff available. 2 hourly or 40 g 4 hourly.'0-12 Immediate management centres around treat- Activated charcoal has been shown to increase ment of heart block with atropine (2-3 mg) and the clearance of digoxin by two mechanisms.""3 temporary pacing. Malignant ventricular dys- Firstly, and of greatest importance, is its effect in rhythmia should be treated with beta-blockers, moderating 'gastrointestinal dialysis' using the lignocaine or phenytoin. Phenytoin (100 mg intra- gastrointestinal wall as a dialysis membrane.""2 venously, repeated after 5 minutes if required) is a Secondly, it interferes with the enterohepatic cir- useful antidysrhythmic as it opposes digitalis bind- culation of digoxin by binding to the drug in the ing and may improve atrioventricular conduction intestinal lumen, resulting in increased elimination by its anticholinergic properties.' Beta-adreno- ofthe recycled drug.'2 Other binding agents such as ceptor blocking agents can terminate glycoside- colestipol and cholestyramine have also been induced ventricular dysrhythmias but are more shown to be effective.""3 In contrast, haemo-copyright. likely to lead to heart block.5-7 Therefore an dialysis and haemoperfusion are clinically ineffec- ultra-short acting intravenous beta-blocker tive.14"15 preparation such as esmolol (half-life, tt= 9 The potential benefits ofsuch an effective, simple minutes) may be useful in these circumstances as its and inexpensive mode of treatment have to be effects may be rapidly reversed.8 Correction of weighed, however, against any resultant morbidity. hypokalaemia is important, generally requiring The major problems are unpalatability of the intravenous supplementation of no more than activated charcoal and the risk of aspiration in http://pmj.bmj.com/ 20 mmol/h of potassium, to reduce digitalis bind- patients who may well be experiencing severe ing to Na/K ATPase."9 More rapid infusion of nausea and vomiting. The treatment of these latter potassium may lead to asystole and concomitant symptoms also poses problems, as the majority of infusion of dextrose may aggravate any hypo- antiemetic agents have concomitant anticholiner- kalaemia.S gic properties, decreasing gastrointestinal motility Cardioversion should be avoided wherever pos- and consequently the concentration gradient sible, due to the risk of precipitating asystole, and across the bowel. Ifthe patient is in a state ofshock when necessary should be attempted using the then reduced splanchnic blood flow will also lead to on September 24, 2021 by guest. Protected lowest energy possible. Elimination of the cardiac reduced gastrointestinal motility. glycoside should then be performed as expeditiously as possible using digoxin-specific Digoxin-specific antibodyfragments antibody fragments. In accidental or deliberate overdosage, general Digoxin-specific fab antibody fragments (Digi- principles oftreatment remain the same. Ifthe drug bind, Wellcome) are possibly the most effective has been ingested within 4 hours the patient should treatment available. However, this therapy is undergo immediate gastric lavage leaving 100 g of expensive and therefore should be reserved for activated charcoal within the stomach. If ingested treatment of serious toxicity, especially in the after 4 hours then the patient should be treated only presence of cardiac dysrhythmias. with activated charcoal. There is evidence that this These antibodies have a high affinity and specifi- therapy is as effective as ipecacuanha-induced city for cardiac glycosides and have been shown to vomiting in preventing drug absorption.'0 reverse digoxin toxicity and reduce the risk of death.'6-18 In several large studies, approximately 80% of patients had complete resolution of all evidence of toxicity, 10% improved whilst 10% Postgrad Med J: first published as 10.1136/pgmj.69.811.337 on 1 May 1993. Downloaded from DIGOXIN TOXICITY 339

showed no response.'6"7 They appear effective for to intracellular shifts ofpotassium, as the effects of all age groups and also in patients with poor renal digoxin are reversed.2 reserve (despite eventual renal elimination).'9 Patients who require redigitalization must wait As with all foreign proteins, anaphylaxis, serum for the complexes to be eliminated from the body sickness or febrile reactions are a source ofconcern, by the kidneys, this taking 2-3 days with normal especially with repeated administration. These renal function.2'2 Unfortunately, fab fragments reactions appear uncommon,2"16"17 for example, in a interfere with both fluorescence excitation transfer study of 717 adults where only six patients (0.8%) immunoassays and radioimmunoassays for digoxin. exhibited any evidence of allergic response.20 This means that serum drug levels cannot be Similarly to streptokinase therapy, repeated monitored until the drug-antibody complexes are administration may possibly be less effective or cleared from the circulation.2224 more hazardous, but no evidence with regard to this matter is currently available. The dose to be administered is calculated on the Conclusion basis of the drug 'load', using the plasma concentration and body weight.2'2' The approximate dose Digoxin toxicity is a common occurrence but for of fab is 60 times the 'load', as the approximate the majority of patients the problem is mild and molecular weight ratio of fab and digoxin is 60.21 effectively managed by symptomatic treatment and Generally improvement in signs and symptoms a reduction in dosage. Where symptoms and signs usually occurs within 30 minutes, with complete are more profound, but without any evidence of resolution of evidence of toxicity within 3-4 serious cardiac toxicity, then regular administra- hours.2 Few adverse effects have been reported with tion of oral activated charcoal is well worth the use of this agent. Nevertheless, theoretically, considering. Development of serious toxicity with patients previously dependent upon the inotropic cardiac involvement requires prompt use of effects of digoxin could develop heart failure and digoxin-specific fab fragments, which can be life hypokalaemia could result within I -5 hours, owing saving. copyright. References

1. Hayward, R. Digitalis: the present position. In: Hamer, J. 14. Slattery, J.T. & Koup, J.R. Hemoperfusion in the manage- (ed.) Drugs for Heart Disease, 2nd ed. Chapman and Hall, ment of digoxin toxicity: is it warranted? Clin Pharmacokinet London, 1987, pp. 145-193. 1979, 4: 395-399. 2. Stolshek, B.S., Osterhout, S.K. & Dunham, G. The role of 15. Warren, S.E. & Fanestil, D.D. Digoxin overdose: limitations digoxin-specific antibodies in the treatment of digitalis of hemoperfusion and hemodialysis. JAMA 1979, 242: poisoning. Med Toxicol 1988, 3: 167-171. 2100-2101. 3. Bayer, M.J. Recognition and management ofdigitalis intoxi- 16. Smith, T.W. Review of clinical experience with digoxin http://pmj.bmj.com/ cation: implications for emergency medicine. Am J Emerg immune Fab (ovine). Am J Emerg Med 1991, 9 (2 Suppl 1): Med 1991, 9 (2 Suppl 1): 29-32. 1-6. 4. Selzer, A. Role of serum digoxin assay in patient manage- 17. Antman, E.M., Wenger, T.L., Butler, V.P., Haber, E. & ment. J Am Coll Cardiol 1985, 5: 106A- 1 A. Smith, T.W. Treatment of 150 cases of life-threatening 5. Smith, T.W., Braunwald, E. & Kelly, R.A. The management digitalis intoxication with digoxin-specific Fab antibody of heart failure. In: Braunwald, E. (ed.) Heart Disease: A fragments. Final report of a multicenter study. Circulation Textbook ofCardiovascular Medicine, 4th ed. W.B. Saunders, 1990, 81: 1744-1752. Philadelphia, 1992, pp. 464-519. 18. Smith, T.W., Butler, V.P., Haber, E. et al. Treatment of 6. George, C.F. Digitalis intoxications: a new approach to an

life-threatening digitalis intoxication with digoxin-specific on September 24, 2021 by guest. Protected old problem. Br Med J 1983, 286: 1533-1534. Fab antibody fragments. Experience in 26 cases. N Engl J 7. Gibson, D. & Sowton, E. The use ofbeta-adrenergic receptor Med 1982, 307: 1357-1362. blocking drugs in dysrhythmias. Prog Cardiovasc Dis 1969, 19. Wenger, T.L. Experience with digoxin immune Fab(ovine) in 12: 16-39. patients with renal impairment. Am J Emerg Med 1991, 9 (2 8. Benfield, P. & Sorkin, E.M. Esmolol. A preliminary review of Suppl 1): 21-23. its pharmacodynamic and pharmacokinetic properties, and 20. Hickey, A.R., Wenger, T.L., Carpenter, V.P. et al. Digoxin therapeutic efficacy. Drugs 1987, 33: 392-412. immune Fab therapy in the management ofdigitalis intoxica- 9. Steiness, E. & Olesen, K.H. Cardiac arrhythmias induced by tion: safety and efficacy results of an observational surveil- hypokalaemia and potassium loss during maintenance lance study. J Am Coil Cardiol 1991, 17: 590-598. digoxin therapy. Br Heart J 1976, 38: 167-172. 21. Digibind Data Sheet. Wellcome Medical Division, The 10. Watson, W.A. Factors influencing the clinical efficacy of Wellcome Foundation Ltd, UK. activated charcoal. Drug Intell Clin Pharm 1987, 21: 160-166. 22. Smith, T.W., Haber, E., Yeatman, L. & Butler, V.P. Reversal 11. Levy, G. Gastrointestinal clearance of drugs with activated of advanced digoxin intoxication with Fab fragments of charcoal. N Engl J Med 1982, 307: 676-678. digoxin specific antibody. N Engl J Med 1976, 294: 797-800. 12. Lalonde, R.L., Deshpande, R., Hamilton, P.P., McLean, 23. Gibb, I, Adams, P.C., Parnham, A.J. & Jennings, K. Plasma W.M. & Greenway, D.C. Acceleration of digoxin clearance digoxin: assay anomalies in Fab-treated patients. Br J Clin by activated charcoal. Clin Pharmacol Ther 1985, 37: Pharmacol 1983, 16: 445-447. 367-371. 24. Natowicz, M. & Shaw, L. Digoxin assay anomalies due to 13. Pond, S., Jacobs, M., Marks, J., Gamer, J., Goldschlager, N. digoxin-specific Fab immunotherapy. Drug Intell Clin Pharm & Hansen, D. Treatment of digitoxin overdose with oral 1991, 25: 739-741. activated charcoal. Lancet 1981, ii: 1177- 1178.