Digitalis Michael

Intoxication Recognition and Management Dick,

MD,

Jay

Curwin,

T

he value of digitalis glycosides in the treatment of cardiovascular diseases has been known to clinicians for centuries, and digoxin remains one of the most commonly prescribed medications in the United States.1 Major indications for digoxin use include atrial fibrillation with a rapid ventricular response, supraventricular tachycardias, and congestive heart failure. The mechanism of action by which digitalis increases cardiac contractility is believed to be via inhibition of the sodium-potassium ATPase pump, with a subsequent increase in myocardial cellular calcium uptake. Antiarrhythmic effects of digitalis glycosides include an increase in atrioventricular (AV) nodal conduction time and refractory period, shortening of atrial refractory periods, and reduction of ventricular muscle refractory periods.2 At the cellular level, these changes are mediated by a digitalis-induced reduction in action potential duration, increases in phase 4 depolarization, and reduction in resting membrane potential. Both the widespread use of digoxin and its diverse mechanisms of action contribute to the high frequency with which digoxin toxicity is seen. Studies have shown an incidence of digitalis intoxication that ranges from 5 to 23%, with mortality reported as high as 41% in one study done 20 years ago. The majority of deaths that are caused by digoxin toxicity are in patients with massive ingestions, often with suicidal intent, and in patients with severe underlying cardiac disease.5 The use of digoxin preparations in lower doses, with more predictable bioavailability and increasing knowledge about other interactions of drugs with digoxin have helped to lower the incidence of toxicity. A review of records at Henry Ford Hospital during the 7-year period ending in 1987 showed that only two percent of patients who received digoxin were

From the Morristown Memorial Hospital (Dr. Dick), Morristown, New Jersey, and the Mount Sinai Medical Center (Drs. Curwin and Tepper), New York, New York. Address for reprints: David Tepper, MD, Division of Cardiology, Box 1030, The Mount Sinai Medical Center, One Gustave L. Levy Place, New York, NY 10029.

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1991;31:444-447

MD,

and

David

Tepper,

MD

believed to be toxic, and interestingly, approximately half of these patients had this problem develop while in the hospital.3 The development of a radioimmunoassay for serum digoxin levels has also made a significant contribution to this declining incidence of toxicity.6 A study performed in Boston several years ago showed a two-fold difference in the frequency of digoxin intoxication between two hospitals, despite similarities in patient characteristics and patterns of digoxin use.7 The only difference that was noted was that serum digoxin measurements were made far more frequently in patients who were taking digoxin in the hospital where there was a lower incidence of toxicity. However, as discussed further later, results of these assays must be interpreted cautiously. In addition to cardiac disease and large ingestions, there are numerous other factors that predispose to digoxin toxicity. Commonly used cardiac medications, including quinidine, verapamil, and amiodarone are known to increase digoxin levels. Hypothyroidism, acid-base imbalances, electrolyte disturbances such as hypokalemia and hypomagnesemia, and active ischemia all increase sensitivity to digoxin.8 Renal insufficiency is also a major contributing factor to digitalis intoxication. The manifestations of digoxin toxicity are multipie and nonspecific. One report published in 1972 examined the side effects experienced by a group of 179 hospitalized patients who were accidently given a combination of .20 mg of digitoxin and .05 mg of digoxin, instead of the prescribed digoxin .25 mg. Fatigue and muscle weakness were found in all but 5% of patients. Visual disorders, including blurriness and changes in color perception, were equally com mon. Nausea with loss of appetite was seen in fourout-of five patients. Other common effects included dizziness, vomiting, and a wide array of psychologic disturbances. Cardiac arrhythmias are responsible for the lifethreatening effects of digoxin toxicity, and frequently occur before any of the noncardiac manifestations.’0 The aforementioned study from the Henry Ford Hospital found that in their patients with di-

DIGITALIS

goxin

toxicity, 53% were in normal sinus rhythm, 31% had atrial fibrillation, and 35% had atrioventricular block. Less commonly seen arrhythmias included AV nodal rhythms, complex ventricular ectopy, and ventricular tachycardia.3 The Digibind Multicenter Trial found a much higher incidence of ventricular tachycardia, seen in 68% of patients, with ventricular fibrillation seen in 49%#{149}h1 Other rhythms that are caused by digoxin toxicity include paroxysmal atrial tachycardia with AV block, and nonparoxysmal junctional tachycardia. Several clinical studies have been done to evaluate the contribution of serum digoxin assays in patient management. A retrospective study of more than 5000 patients12 who received digoxin showed an increased mortality rate which correlated with higher serum levels, with up to 50% mortality in patients with a level more than 6.0 ng/mL. On the other hand, there was a poor correlation between serum levels and the signs, symptoms, and ECG changes of digoxin toxicity. Another study examined request patterns for serum digoxin levels, and found that in more than 40% of cases the tests could not be interpreted, frequently because of improper sampling time.’3 Therapeutic action was taken in almost two-thirds of the patients with these improperly timed specimens. The significance of “subtherapeutic” digoxin levels was uncertain, with a wide variety of actions taken in response to these levels. Variability in individual patient sensitivity adds to the difficulty in interpreting serum assay values. The proper sampling time for serum digoxin measurements has been studied.14”5 Based on pharmacokinetic principles, samples should not be obtained for at least 6 hours from the time the last dose was given. In fact, serum concentrations may double in the first few hours after the last dose. If a sample was taken before 6 hours, nomograms exist that can be used to help correlate a given reported value with an estimated steady-state concentration of digoxin.15 Another possibly confounding factor in the measurement of digoxin levels has been the detection of endogenous digoxin-like substances in the sera of patients.16”7 These substances have been found in normal subjects but have been shown to be less proteinbound (and therefore, more detectable in serum assays) in the sera of patients with renal failure, hepatobiliary disease, in newborns, and in pregnant women. MANAGEMENT Successful pends on

OF

DIGITAUS

management early recognition

CARDIOVASCULAR

TOXICITY

of digitalis intoxication of digitalis as the

decause

INTOXICATION

for the presenting clinical picture. Assessment is based on clinical evaluation-taking into account symptoms, electrocardiographic (ECG) dysrhythmias, and response to pharmacologic manipulation -as well as careful interpretation of serum digitalis measurements. Once a diagnosis of digitalis intoxication is made, the patient should be risk-stratified to determine appropriate treatment. Low-risk patients are those without evidence of ECG rhythm disturbances and with only mildly elevated serum levels. These are patients without a history of severe cardiac disease, those with good left ventricular function and are usually taking digoxin for uncomplicated atrial fibrillation. If clinically appropriate, this population can be treated as outpatients by temporarily withholding digitalis and repeating ECGs to look for the effects of digitalis withdrawal. Intermediate risk includes cardiac toxicity that is confirmed by ECG in patients without life-threatening complications. These patients merit observation in a monitored setting. Potassium and magnesium levels should be obtained and careful replacement therapy should be provided if marked hypokalemia or hypomagnesemia is noted. However, because of inhibition of the plasma membrane sodium-potassium ATPase pump, severe and life-threatening hyperkalemia may ensue in the setting of digoxin toxicity.’8”91n addition, potassium administration may exacerbate AV block and should be done cautiously in the patient with this condition or with sinus bradycardia without high-grade ventricular ectopy. Metabolic alkalosis results in the redistribution of potassium intracellularly and increases renal excretion of potassium. Hypercalcemia (like hypokalemia and hypomagnesemia) has also been shown to increase ventricular automaticity and may warrant the use of calcium-chelating agents. Antiarrhythmic drug therapy should generally be avoided unless hemodynamically significant dysrhythmias or high grade ectopy exits. High-risk patients include those with extremely elevated serum digitalis levels, and those with lifethreatening arrhythmias. These patients warrant admission to a coronary care unit for more careful observation. If oral ingestion has occurred within 6 to 8 hours, the stomach should be evacuated and a charcoal slurry should be administered. Digitoxin undergoes some enterohepatic circulation2#{176} and anion exchange resins may be given to shorten its half-life. Cholestyramine interferes with the initial absorption of digoxin from the gastrointestinal tract. Marked sinus bradycardia, sinoatrial arrest, and second- or third-degree heart AV block are sometimes treated effectively with atropine. Occasionally, in-

445

DICK,

CUR WIN,

sertion of a temporary pacemaker may be considered in a patient who is hemodynamically unstable and not responding to atropine. Premedication with lidocaine should be provided because the cardiac muscle is already predisposed to the initiation of tachydysrhythmias, and pacemaker insertion may act as an additional irritant. Lidocaine and phenytoin are the most useful antiarrhythmic agents for the treatment of digitalis-induced cardiac dysrhythmias.21 Lidocaine is given intravenously, and is efficacious against ventricular dysrhythmias in part by increasing the fibrillation threshold, and by inhibiting cardiac sympathetic nerve activity. Phenytoin may be given by mouth or by vein and is effective in both atrial and ventricular dysrhythmias that are caused by digitalis toxicity. Although procainamide may be administered intravenously for the treatment of supraventricular and ventricular dysrhythmias, it must be given with caution because it, like digitalis, depresses AV nodal and His-Purkinje conduction. Procainamide also has a modest negative inotropic effect and may stimulate ventricular dysrhythmias. Quinidine has no role in the treatment of digitalis toxicity. This drug may raise serum digoxin levels, has a greater negative motropic effect than procainamide, and has a significant proarrhythmic effect. A characteristic quinidine-induced dysrhythmia is polymorphic ventricular tachycardia, or torsade de pointes. Direct current cardioversion is relatively contraindicated in the patient with digitalis toxicity. Although the shock may interrupt the electrical focus that is involved in maintaining the tachycardia, the underlying suppression of the AV node by digitalis may result in severe ventricular dysrhythmias.22 If electric cardioversion is mandated, low energy should be used because higher levels lead to prolonged arrest of the sinoatrial (SA) and AV nodes, and may cause ventricular arrhythmias, including ventricular fibrillation. Papamn-cleaved Fab fragments of sheep derived digoxin-specific antibodies (Digibind) have been approved for use in the United States since 1986 and are proving to be highly effective in the treatment of life-threatening digitalis intoxication.112326 The Fab fragments have the following advantages over intact antibody molecules: 1) rapid distribution with better access to tissue digitalis binding sites, 2) less immunogenicity and risk of allergic reaction, and 3) more rapid elimination via glomerular filtration and urinary excretion.27 Circulating ovine Fab fragments are able to bind immediately and inactivate circulating digitalis, resulting in near zero levels of free digitalis. This effect establishes a concentration gradient, which promotes a release of digitalis from receptor

446

#{149} .J ClIn Pharmacol

1991;31:444-447

AND

TEPPER

sites as the free serum-receptor bound equilibrium is displaced in the direction of dissociation. As a result, the cardiac rhythm of the patient typically starts to improve after 15 to 30 minutes.1’ The fall in the free digitalis serum concentration level is followed by a rapid rise in bound (inactive) digitalis. In patients with normal renal function, the Fab digitalis immune complex has a 16 to 20 hour serum halflife.5 In patients with significantly impaired renal function, the serum half-life of the bound (inactive) digitalis is approximately twice that observed in patients with normal glomerular function.28 As a result, serum levels after Fab fragment administration are of little value for several days since most of the digitalis remains bound and inactive. The use of digitalis immune Fab fragments should be considered when other modes of treatment are proved or anticipated to be inadequate in patients with life-threatening dysrhythmias that are caused by digitalis intoxication. One may also consider their use in digitalis-toxic patients with rising potassium concentrations, because Digibind is the only pharmacologic agent effective in treating digitalis-induced hyperkalemia. Finally, there may be clinical situations where a patient who is receiving digitalis has recurrent dysrhythmias, and the rapid elimination of digitalis through Digibind may help aid in diagnosis. The dosage of Digibind is based on the estimation of the total body load of digitalis of the patient. Calculation is based either on 1) the steady-state serum digitalis concentration, or 2) an accurate knowledge of the number of digitalis tablets or capsules that were ingested.29 Using the serum concentration, one calculates: Total

body

load

(mg)

=serum

digitalis

concentration X

5.6 X weight

(kg)/1000

where 5.6 L/kg represents the volume of distribution of digoxin. One substitutes 0.56 1/kg in this calculation when digitoxin is ingested. For treating toxicity from an acute ingestion without knowing the steady-state serum concentration, the following formula is used: Total

body =

load

amount

(mg) ingested

(mg)

X

0.8 (bioavailability)

Each vial of Digibind contains 40 mg, which can bind approximately 0.6 mg of digitalis. Therefore, the number of vials that are required equals total body load (mg)/0.6 (mg/vial). The manufacturer advises that for acute ingestions of unknown quantities of

DIGITALIS

INTOXICATION

digitalis in patients with unknown serum concentrations, 20 vials will be effective most of the time. Although frequently administered by vein over 15 to 30 minutes through a 0.22 micrometer membrane filter, Digibind may be given as a bolus injection in emergencies. Once Digibind is administered, the following precautions should be taken: 1) check repeatedly for hypokalemia in the first few hours, 2) observe for evidence of congestive heart failure from loss of digitalis-mediated inotropy, and 3) monitor for allergic reactions, particularly in patients with known allergy to sheep proteins and in patients who have previously been given digitalis immune Fab. CONCLUSIONS Because of a revitalized interest in the use of digoxin for the treatment of congestive heart failure, and the well-documented efficacy of digoxin as therapy for atrial fibrillation and supraventricular tachycardias, we will continue to see patients who are suffering from the toxic effects of this drug. Our use of lower doses and more predictable digitalis preparations has served to decrease the incidence of this common clinical problem, as has the development of fast and accurate radioimmunoassays for the measurement of serum concentrations. The diagnosis of digoxin intoxication is still primarily a clinical one, and assays should both be ordered and interpreted with due care. Although most patients can be treated safely with careful monitoring of cardiac rhythm and electrolytes,

life-threatening

cases

to other by the

measures administration

are refractory aged effectively Fab fragments.

of toxicity

can

which

1. Clarke W, Ramoska EA: Acute digoxin overdose: Use of digoxin-specific antibody fragments. Am J Emerg Med 1988;6:465470. 2. AMA Drug Evaluations, 5th Edition, 1985;602. 3. Gheorghiade M, Rosman H, Mahdyoon H, Goldstein S: Incidence of digitalis intoxication. Prim Cardiol Special Edition No. 1, 1988;5-11. 4. Beller GA, Smith TW, Abelmann WH: Digitalis intoxication: A prospective clinical study with serum level correlations. N Eng I Med 1971;284:990-997. 5. Wenger T, Butler VP, Haber E, Smith TW: Treatment of 63 severely digitalis-toxic patients with digoxin-specific antibody fragments. I Am CoIl Cardiol 1985;5:118A-123A.

CARDIOVASCULAR

J: Reduction of serum Surveillance

9. Lely AH, van Enter CHJ: Non-cardiac symptoms intoxication. Am Heart J 1972;83:149-152. 10. Doherty JE: Use of digitalis and diuretics in the heart failure, in, Cohn JN Drug Treatment of Heart Edition, 1988;154.

of digitalis treatment Failure,

of 2nd

11. Wenger TL: Clinical experience with digoxin immune fab (Ovine). Prim Cardiol Special Edition No.1, 1988;19-23.7. Clinical experience with digoxin immune fab (Ovine). Prim Cardiol Special Edition No. 1, 1988, 19-23. 12. Ordog GJ, Benaron tality in 5,100 patients.

S. Bhasin V: Serum digoxin levels Ann Emerg Med 1987;16:32-39.

and mor-

13. O’Donnell JG, Paterson NC, Pledger DR: Serum digoxin assays: investigation of use and abuse. Ann Ciin Biochem 1987;24:408-410. 14. Gibb I, Cowan JC, Parnham AJ: Use and misuse of a digoxin assay service. Br Med J 1986;293:678-680. 15. Nicholson PW, Dobbs SM, Rodgers EM: Ideal sampling time for drug assays. Br J Clin Pharmocol 1980;9:467-470. 16. Wickramasinghe LSP, Bansal SK, Dillon RDS: ‘Digoxin-Like’ Substance in Serum of Elderly Patients. Age Ageing 1986;15:271277.

17. Valdes R: Endogenous digoxin-like Impact on digoxin measurements and plications. Clin Chem 1985;31:1525-1532.

immunoreactive factors: potential physiological im-

18. Bismuth C, Gaultier M, Conso F: Hyperkalemia in acute digitalis poisoning: Prognostic significance and therapeutic implications. Clin Toxicol 1973;6:153-162. 19. Smith TW, Willerson JT: Suicidal gestion: Report of five cases with serum Circulation 1971;44:29-36.

and accidental digoxin level

digoxin incorrelations.

20. Hoffman BF, Bigger JT: Digitalis and allied cardiac glycosides, in, Goodman and Gillman’s The Pharmacologic Basis of Therapeutics, 7th Edition. New York: MacMillan Publishing Co., 1985;71621. Bigger JT, Strauss HC: Digitalis toxicity: Drug interactions moting toxicity and the management of toxicity. Semin Treatment 2 1972;147-177. 22. Kleiger R, Lown B: Cardioversion and digitalis II: Clinical ies. Circulation 1966;33:878-887.

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6. Smith TW, Butler VP, Haber E: Determination of therapeutic and toxic serum digoxin concentrations by radioimmunoassay. Eng J Med 1969;281:1212-1216.

8. Friedman PL: Factors in individual sensitivity sides and recognition of digitalis intoxication. cial Edition No. 1, 1988;13-17.

N

of dilevels: A Program.

proDrug stud-

23. Spiegel A, Marchlinski FE: Time course for reversal of digoxin toxicity with digoxin-specific antibody fragments. Am Heart I 1985;109:1397-1399. 24. Smith TW, Butler VP, Haber E: Treatment of life-threatening digitalis intoxication with digoxin-specific Fab antibody fragments: Experience in 26 cases. N Engl I Med 1982;307:1357-.1362. 25. DeSantola JR, Marchlinski FE: Response of digoxin toxic atrial tachycardia to digoxin-specific Fab fragments. Am J Cardiol 1986;58:1109-1110. 26. Smith TW, Haber E, Yeatman L, Butler VP: Reversal of advanced digoxin intoxication with Fab fragments of digoxin-specific antibodies. N Eng J Med 1982;307:1357-1362. 27. Lloyd BL, Smith TW: toxicity by digoxin-specific 1978;58:280-283.

Contrasting lgG and

rates of reversal Fab fragments.

of digoxin Circulation

28. Dunham G, Calif RM: Digoxin toxicity in renal insufficiency treated with digoxin immune Fab: Case summaries of two patients. Primary Cardiology Special Edition No. 1, 1988;31-34. 29. Burroughs Wellcome Co.: The only antidote for digitalis intoxication. 1989.

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Digitalis intoxication recognition and management.

Digitalis Michael Intoxication Recognition and Management Dick, MD, Jay Curwin, T he value of digitalis glycosides in the treatment of cardiovas...
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