Recognition and Management of Digitalis Intoxication: Implications for Emergency Medicine MARC J. BAYER,
MD
Digitalis intoxication is among the most common serious adverse drug reactions in clinical medicine. While the recent development of a radioimmunoassay to accurately measure serum concentrations of digoxin has been of assistance, digitalis intoxication remains a difficult diagnosis to make with certainty. The difficulty in diagnosing digitalis intoxication arises from the nonspeciffcity of its associated signs and symptoms. The most common symptoms include fatigue, weakness, nausea, and anorexia. These symptoms can occur with many illnesses other than digitalis intoxication. Similarly, the electrocardiographic disturbances caused by cardiac glycosides may be nondiagnostic. The arrhythmias commonly associated with digitalis toxicity are often nonspecific and can be a reflection of the patient’s underlying heart disease. The measurement of serum digoxin levels is useful, but studies have demonstrated overlap of the levels between groups with and without toxicity. Due to the modulation of the cardiac effects of digitalis glycosides by such clinical variables as underlying myocardial or renal disease, electrolyte and acid-base imbalances, and other factors, the correlation of toxicity with particular serum digoxin concentrations may vary. Because of the inherent difficulties in confirming the diagnosis of digitalis intoxication in some cases, digoxin-specific Fab antibodies may play a role as a diagnostic tool. Certainly, digoxin-specific Fab antibodies play a significant part in the treatment of digitalis intoxication. Fab antibodies have been successfully used to reverse the effects of digoxin, digitoxin, and oleander poisoning. These antibodies are useful in the treatment of acute and chronic digitalis intoxication in all age groups, including geriatric and pediatric populations. Digoxin-specific Fab antibodies have a high degree of specificity to digoxin, and their administration causes rapid lowering of free serum digoxin to minuscule levels. Allergic reactions to digoxin-specific Fab antibodies are infrequent. The benefit of these antibodies has been demonstrated in numerous case reports and clinical trials. A review of 150 cases compiled over a 13-year period found approximately 80% of patients suffering from advanced digitalis intoxication responded completely to treatment with Fab fragments; another 10% improved substantially. This article will review the current scientific reasoning concerning the diagnosis and management of digitalis intoxication and the expanding role of digoxin-specific Fab antibodies. (Am J Emerg Med 1991;9:29-32 [suppl 11. Copyright Co 1991 by W.B. Saunders Company) The foxglove when given in very large and repeated doses occasions sickness, vomiting, purging. giddiness, confused vision. objects appearing green or yellow: increased secretion of urine, with frequent motions to part with it. and sometime inability to retain it; slow pulse, even as slow as 35 beats in a minute. cold sweats. convulsions, syncope. death.’ Since 1785. when William Withering tirst described the adverse effects of foxglove. the plant from which digitalis is derived.
From the Department of Medicine, UCLA School of Medicine, Department of Emergency Medicine, Olive View/UCLA Medical Center, Los Angeles Poison Center, Los Angeles, CA. Address reprint requests to Dr Bayer, 14445 Olive View Drive, Sylmar, CA 97342. Key Words: Digitalis intoxication, digoxin-specific Fab antibodies, Fab antibodies. Copyright (P 1991 by W.B. Saunders Company 0735-6757/91/0902-1007$5.00/O
physicians have been repeatedly called on to treat patients suffering from digitalis intoxication. Digoxin’s wide use. coupled with its inherent toxicity. make this drug one of the more common candidates for serious accidental and deliberate overdose, both chronic and acute. Currently, digoxin is the I lth most frequently prescribed medication in office practice in the United States.’ Estimates of toxicity in digitalized patients vary from 6% to 23%, with specific signs and symptoms depending on the general health of the patient and on whether the toxicity is acute or chronic.3-b Most often. toxicity occurs in patients on longterm cardiac glycosides: however, there are numerous reports of acute overdose in healthy patients.7.8 Fatalities occur in all age groups. In the past. treatment of digitalis intoxication has been hindered by difficulties in diagnosis as well as the lack of a specific antagonist to reverse life-threatening complications. Better recognition of the subtle manifestations of digitalis poisoning will lead to more prompt institution of therapy. Today, the therapeutic arsenal designed to combat digitalis intoxication has been boosted considerably by the addition of digoxin-specific Fab antibodies. The results of a I3-year multicenter trial involving 150 patients treated with Fab antibodies for life-threatening digitalis intoxications demonstrate the usefulness of this new antidote.’ This study and others presented in this supplement detail a comprehensive and current overview on the recognition and management of digitalis intoxications. The highlights of this information and its implications for emergency medicine specialists are provided in this article. RECOGNITION
OF DIGITALIS
INTOXICATION
The diagnosis of digitalis intoxication can be difficult for several reasons: (I ) the associated signs and symptoms are often subtle and nonspecific; (2) electrocardiographic (ECG) findings of cardiac manifestations are often nonspecific: (3) serum digoxin concentrations do not always correlate with toxicity. Each of these factors are discussed in more detail below. Signs and Symptoms The signs and symptoms of digitalis intoxication can be separated into cardiac and extracardiac manifestations. There are a multitude of extracardiac manifestations associated with excess digitalis that are nonspecific and can be confused with other disease states. Most of these symptoms are related to the central nervous system and gastrointestinal tract. The incidence of such symptoms is difficult to quantify, but as a result of a pharmaceutical formulation error in 1970 in the Netherlands, researchers were able to identify the most common symptoms of digitalis intoxication.” One hundred seventy-nine patients developed digitalis toxicity from receiving tablets that contained 0.2 mg of digitoxin as well as 0.05 mg of digoxin instead of the intended 0.25 mg of digoxin. The two most common symptoms reported 29
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were fatigue (95%) and visual symptoms (95%) such as seeing halos of light or enhanced perception of yellow and green colors. Other common symptoms reported were weakness (82%), nausea (8 1%). and anorexia (80%). Gastrointestinal symptoms are frequent in both acute and chronic digitalis toxicity. Anorexia, nausea, and vomiting have an incidence ranging from 30% to 80%.4,‘o,’’ Anorexia can occur relatively early in digitalis intoxication, often preceding nausea and vomiting.‘* Gastrointestinal symptoms usually present early in the course of an overdose and are thought to be centrally mediated, as they are seen with both intravenous and oral preparations.13 Gastrointestinal symptoms appear to occur with the same frequency in all age groups. Wofford and Ettinger, in an evaluation of the Digibind@ Postmarketing Surveillance Study, suggested that in cases of life-threatening toxicity, there is no age-related difference in the incidence of nausea and vomiting.14 In elderly patients in particular, it can be difficult to distinguish the gastrointestinal symptoms of digitalis toxicity from those caused by other medical conditions. Neurological and visual manifestations occur in both acute and chronic toxicity. “J Neurological signs and symptoms range from malaise, headache, fatigue, depression, or confusion to hallucinations and delirium. Visual disturbances present as blurring and alterations in color and pattern vision.16 Most of the neurological manifestations of digitalis intoxication are nonspecific and can mimic other disease entities. Toxic neuropsychiatric manifestations of digoxin can occur at therapeutic concentrations rendering the diagnosis even more difficult.17 Both neurological and visual manifestations may persist after other signs of toxicity have resolved.6 Cardiac manifestations are the life-threatening complications of digitalis intoxication. Arrhythmias can be due to depression or blockade of conduction and/ or enhanced impulse formation. Enhanced impulse formation may appear in the form of atrial, junctional, or ventricular arrhythmias. Disturbances of conduction can occur in the sinus and atrioventricular node. Interference with sinus node conduction takes the form of sinus bradycardia, sinus arrest or sinoatrial block. Significant depression of conduction at the atrioventricular (AV) node can present as second- and third-degree AV block. Second-degree block usually manifests as Wenkebach; Mobitz II is uncommon in digitalis toxicity. Early toxicity may present with prolongation of the PR interval.” Atria1 tachycardia with heart block is caused by both disturbances in conduction and enhanced impulse formation.14 In an otherwise healthy patient suffering from an acute overdose, ventricular arrhythmias or ectopy are uncommon.‘5.‘9 The healthy myocardium often responds to digitalis excess with the development of AV conduction disturbances.” Conversely, the diseased heart frequently responds with ectopic impulse formation particularly from ventricular foci.” Digitalis excess can cause a wide variety of arrhythmias. Rhythms less likely to be caused by digitalis intoxication include atria1 fibrillation with a rapid irregular ventricular response and wide complex regular ventricular tachycardia.” Although bradyarrhythmias are not specific for digitalis excess, certain tachyarrhythmias are characteristic of digoxin intoxication. These include atria1 tachycardia with variable AV block, accelerated junctional rhythms (especially in the setting of atria1 fibrillation), and fascicular tachycardia.*’ Acute digoxin overdoses result in hyperkalemia as a result of poisoning of the membrane-bound sodium potassium pump.
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This selective poisoning results in increased extracellular and decreased intracellular potassium, thus reducing the normal resting membrane potential. Consequently, the myocardial cells lose their ability to function as pacer cells, and blocks or asystole result.*’ The degree of hyperkalemia in acute digitalis overdoses may have some predictive value of patient outcome. Gaultier and Bismuth reported a mortality rate of 35% for digitalis intoxicated patients who had a potassium greater than 5 mEq/L and who were treated by conventional means.” However, in chronic toxicity, the potassium is usually normal or low. Potassium can be depleted by diuretics, which are prescribed along with digoxin for the treatment of heart failure. Hypokalemia increases the binding of digoxin to myocardial receptors and is a predisposing factor in the development of digitalis toxicity.‘4 Other conditions predisposing to digitalis intoxication include hypomagnesemia, advanced heart disease, chronic pulmonary disease, and concomitant drug administration such as quinidine and verapamil.20.23
Serum Digoxin Concentration levels Most clinical laboratories use a radioimmunoassay (RIA) technique to measure serum digoxin concentration levels. The development of radioimmunoassay to quantitate serum concentrations of digoxin or digitoxin accurately and reproducibly has been an important step in the improved capability to diagnoses digitalis intoxication. 24 However, there are limitations in correlating serum digoxin concentration levels with clinical toxicity. Most studies have demonstrated considerable overlap of serum digoxin levels between groups with and without toxicity.24 The time that the test was drawn in relation to when the overdose occurred is important. Serum digoxin levels obtained soon after an overdose may not accurately reflect toxicity, as the drug may still be in the distribution place. There are a number of variables that may affect the sensitivity of individual patients to digitalis. Pediatric patients appear to be more resistant to the cardiotoxic effects of digoxin than adults at comparable levels.25 Springer et al reported an 1&month-old child who after a massive digoxin overdose had a serum digoxin level of 48 ng/mL. This child developed only mild manifestations of digitalis toxicity.26 Alternately, patients with advanced myocardial disease, electrolyte imbalances, or hypothyroidism may be more sensitive to digitalis and develop toxicity at “normal” ranges of serum digoxin concentration levels. Finally there are endogenous digoxinlike substances (EDLS) that have been reported to cause false-positive digoxin values in newborns, pregnant women, and adults with kidney and liver disease.27.28 Thus, the physician must use clinical judgement in assessing patients with possible digitalis intoxications; no single laboratory value should be solely relied on to make a diagnosis.
MANAGEMENT OF OIGITALIS INTOXICATION Prior to the use of digoxin-specific Fab antibodies, treatment of digitalis intoxication was largely supportive. Currently, supportive measures remain the cornerstone of therapy. Once the patient has been stabilized, the usual modalities for gastric decontamination (ipecac, lavage, charcoal, cathartic) are used for acute overdose. Because both emesis and lavage may increase vagal tone thereby worsening AV block or bradycardia, pretreatment with atropine has been recommended.6 Multiple dose charcoal has been recommended for digitoxin, which undergoes significant enterohepatic recirculation, as well as for digoxin.29
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However, the clinical effectiveness of serial charcoal in the treatment of digitalis intoxication has not been established. Procedures designed to enhance elimination such as forced diuresis, hemodialysis, and hemoperfusion are of limited usefulness due to digoxin’s high volume of distribution. Conventional treatment of severe hyperkalemia in acute overdose patients consists of administering glucose, insulin, and bicarbonate to force potassium into the intracellular space. The management of arrhythmias is directed toward the cause of the rhythm disturbance. Disturbances of impulse conduction with bradycardia compromising hemodynamic stability are treated with atropine and, if necessary, a pacemaker. Phenytoin and lidocaine are the agents of choice in managing arrhythmias characterized by enhanced automaticity (ventricular premature beats, ventricular tachycardia). Phenytoin is also effective in converting atria1 tachycardia with block to sinus rhythm. Phenytoin is particularly useful as an antiarrhythmic for digitalis intoxication because it enhances depressed AV nodal conduction. Quinidine and procainamide (type I, antiarrhythmics) should not be used as they can severely depress conduction in the SA node, AV node, and His-Purkinje tract and consequently can worsen digitalis-induced arrhythmias.” Therapy for digitalis intoxication has advanced significantly with the introduction of a specific antidote to reverse life-threatening complications. Digoxin-specific Fab antibodies, first used to reverse human poisoning in 1976.30 have proven to be safe and markedly effective. A recently concluded multicenter trial of 150 patients with life-threatening digitalis intoxication treated with Fab antibodies provided conclusive evidence of their efficacy and safety.’ The patients, suffering from both acute and chronic overdoses, ranged in age from I day to 94 years old. The intoxications were severe. The median ingested dose of digoxin in acute overdoses was 12.5 mg. The median serum digoxin level was 8.0 ng/mL. Life-threatening complications included refractory ventricular tachycardia (46%). ventricular fibrillation (33%). high-grade AV block (53%). and hyperkalemia (37%). Treatment with digoxin specific antibodies resulted in striking improvement in most patients. Eighty percent of the patients had complete resolution of their intoxication, and 10% demonstrated improvement of their signs and symptoms. Most dramatic were the number of patients who were successfully resuscitated from cardiac arrest. Thirty of 56 patients (54%) whose digitalis toxicity led to cardiac arrest survived hospitalization. This survival rate using Fab antibodies compares favorably to the 100% mortality of digitalis induced cardiac arrest when patients were treated with conventional therapy alone. 3’ An observational surveillance study of an additional 7 17 digitalis intoxicated patients treated with Fab antibodies demonstrated that 74% of patients had a complete or partial response to the antibodies.3” There were no allergic responses in the multicenter trial and 6 cases ofan allergic skin rash in the observational surveillance study. Allergic manifestations occurred in less than 1% of patients. Other adverse events related to Fab included hypokalemia, worsening of congestive heart failure, and increased ventricular rate of patients with atrial fibrillation. These phenomena occurred in less than lW% of patients?’ Based on the evidence to date, digoxin-specific Fab antibodies are safe and effective. Prior to the conclusion of studies confirming their safety and efficacy. Fab antibodies were recommended for use in digitalis intoxication with potentially life-threatening arrhythmias and/or hyperkalemia after standard therapy had
failed. Clearly. these earlier guidelines need revision. Digoxinspecific Fab antibodies should be administered as early as possible in the course of a life-threatening digitalis intoxication. Physicians treating this entity should not wait for the failure of conventional therapeutic measures before deciding to use Fab antibodies. This antidote should be promptly given to those patients suffering from digitalis induced ventricular arrhythmias. high-grade AV block, and/or severe hyperkalemia (potassium concentrations greater than 5 mEq/L). Similarly, Fab antibodies should be administered to patients in cardiac arrest suspected of digitalis intoxication. If the dose of digoxin ingested is established as potentially life-threatening (Rumack reports this as greater than 10 mg in a healthy adult and greater than 4 mg in a healthy child33) and signs of cardiac toxicity are apparent, then Fab antibodies should be administered. Digoxin serum concentrations may be of use in predicting severe toxicity and assessing the need for Fab antibodies. Ordog et al in a retrospective review of 5.100 patients on digoxin, reported a mortality rate of 50% in those patients with serum digoxin levels greater than 6 ng/mL.34 Given this high mortality rate, it would be prudent to seriously consider Fab antibodies for those patients with signs of cardiac toxicity and postdistribution serum digoxin levels of greater than 6 ng/mL. The threshold for administering digoxin specific Fab antibodies is lower in infants and the elderly as well as patients with underlying heart or lung disease. It is essential that patients suffering from digitalis intoxications be closely monitored and observed. If Fab antibodies are administered, total serum digoxin concentration levels rise significantly and cannot be used to guide therapy. Potassium levels have to be monitored carefully as Fab can produce hypokalemia. Hypokalemia can become an even more serious problem if treatment measures (such as glucose. insulin, and bicarbonate) have been instituted for hyperkalemia in addition to Fab. Other adverse events with Fab. such as worsening of congestive heart failure or an increase in ventricular rate in patients with atria1 fibrillation, can occur from loss of digitalis effect. In essence, however. the benefits of digoxin-specific Fab antibodies far outweigh the risks. The emergency physician now has a specific antidote that can dramatically reduce the morbidity and mortality associated with the cardiotoxic effects of digitalis. REFERENCES 1. Withering W: An account of the foxglove and some of its medical uses; with practical remarks on dropsy, and other diseases. Facsimile reprint of 1785 ed. Birmingham, AL: The Classics of Medicine Library. Gryphon Editions Ltd, 1979, p 184 2. Sueta C, Carey T, Burnett C: Reassessment of indications for digoxin. Arch Intern Med 1988;149:609-612 3. Smith TW, Harker E: Digitalis. N Engl J Med 1973;289:11251128 4. Belier GA, Smith TW, Abelman WI-I: Digitalis intoxication. A prospective clinical study with serum correlation. N Engl J Med 1971;284:989-996 5. Elkins BR, Wantabe AS: Acute digoxin poisonings. Am J Hosp Pharm 1978;35:268-277 6. Sharff JA, Bayer MJ: Acute and chronic digitalis toxicity: Presentation and treatment. Ann Emerg Med 1982;11:327-331 7. Propp DA, Hogan T, Mattimore J: Nausea, dyspnea, and heart block in an 86-year-old patient with congestive heart failure. Ann Emerg Med 1988;17:261-267 8. Litovitz TH. Schmitz BF. Helm KC: 1988 annual report of the American Association of Poison Control Centers National Data Collection System. Am J Emerg Med 1988;7:495-545
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9. 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-l 752 10. Lely AH, Van Enter CHJ: Large scale digitoxin intoxication. Br Med J 1970;3:737-740 11. Dubnow MH, Burchell B: Comparison of digitalis intoxication in two separate periods. Ann Intern Med 1915;62:956-965 12. Smith TW, Antman EM, Friedman PL, et al. Digitalis glycosides: Ill. Mechanisms and manifestations of toxicity. Prog Cardiovasc Dis 1984;27:21-55 13. Mason DT, Zellis R, Lee G, et al: Digitalis toxicity. Am J Cardiol 1971;27:546-559 14. Wofford JH, Ettinger WH: Risk factors and manifestations of digoxin toxicity in the elderly. Am J Emerg Med 1991;9:1 l-l 5 (suppl 1) 15. Fowler RS, Rath L, Keith JD: Accidental digitalis intoxication in children. J Pediatr 1964;64:188-199 16. Volpe BT, Soave R: Formed visual hallucinations as digitalis toxicity. Ann Intern Med 1979;91:856-866 17. Eisendrath SJ, Sweeney MA: Toxic neuropsychiatric effects of digoxin at therapeutic serum concentrations. Am J Psychiatr 1987;144: 506-507 18. Chuny EK: Digitalis Intoxication. Baltimore, MD, Williams and Wilkins, 1969, pp, 58-68 19. Smith TW, Willerson JT: Suicidal and accidental digoxin ingestion Circulation 1971;44:29-36 20. Marchlinski FE, Hook BG, Callans DJ: Which cardiac disturbances should be treated with digoxin immune Fab antibody? Am J Emerg Med 1991;9:24-28 (suppl 1) 21. Doherty HE: How and when to use the digitalis serum levels. JAMA 1978;239:2594-2596
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22. Gaultier M, Bismuth C: L’intoxication digitalique aigue. La Rev d Practicien 1978;28:4565-4579 23. Smith TW, Haber E: Digitalis intoxication, clinical presentation and serum concentration. J Clin Invest 1969;49:2377-2386 24. Smith TW, Antman EM, Friedman PL, et al: Digitalis glycosides: I. Mechanisms and manifestations of toxicity. Prog Cardiovasc Dis 1984;26:413-441 25. Lewander WJ, Gaudreault P, Einhorn H, et al: Acute pediatric digoxin ingestion: A ten-year experience. Am J Dis Child 1986;140: 770-773 26. Springer M, Olson K, Feaster W: Acute massive digoxin overdose: Survival without use of digitalis-specific antibodies. Am J Emerg Med 1986;4:364-368 27. Graves SW, Brown B, Valdez R: An endogenous digoxin-like substance in patients with renal impairment. Ann Intern Med 1983;99: 604-608 28. Pudek MR, Seccombe DW, Whitefield MF: Digoxin-like immunoreactivity in premature and full-term infants not receiving digoxin therapy. N Engl J Med 1983;308:904-905 29. Boldy DAR, Smart V, Vale JA: Multiple doses of charcoal in digoxin poisoning. Lancet 1985;2:1076-1077 30. Smith TW, Haber E, Yeatman A, et al: Treatment of life-threatening digitalis intoxication with digoxin-specific Fab antibody fragments, N Engl J Med 1982;307:1359-1362 31. Gaultier M, Bismuth C: L’intoxication digitalique aigue. La Rev d Practicien 1978;28:4565-4579 32. Smith TW: Review of clinical experience with digoxin immune fab (ovine). Am J Emerg Med 1991;9:1-6 (suppl 1) 33. Rumack 8: Cardiac glucosides. Poisindex 1990; 65 34. Ordog G, Benaron S, Bhasin V: Serum digoxin levels and mortality in 5,100 patients. Ann Emerg Med 1987;16:32-39
MD
Digitalis intoxication is among the most common serious adverse drug reactions in clinical medicine. While the recent development of a radioimmunoassay to accurately measure serum concentrations of digoxin has been of assistance, digitalis intoxication remains a difficult diagnosis to make with certainty. The difficulty in diagnosing digitalis intoxication arises from the nonspeciffcity of its associated signs and symptoms. The most common symptoms include fatigue, weakness, nausea, and anorexia. These symptoms can occur with many illnesses other than digitalis intoxication. Similarly, the electrocardiographic disturbances caused by cardiac glycosides may be nondiagnostic. The arrhythmias commonly associated with digitalis toxicity are often nonspecific and can be a reflection of the patient’s underlying heart disease. The measurement of serum digoxin levels is useful, but studies have demonstrated overlap of the levels between groups with and without toxicity. Due to the modulation of the cardiac effects of digitalis glycosides by such clinical variables as underlying myocardial or renal disease, electrolyte and acid-base imbalances, and other factors, the correlation of toxicity with particular serum digoxin concentrations may vary. Because of the inherent difficulties in confirming the diagnosis of digitalis intoxication in some cases, digoxin-specific Fab antibodies may play a role as a diagnostic tool. Certainly, digoxin-specific Fab antibodies play a significant part in the treatment of digitalis intoxication. Fab antibodies have been successfully used to reverse the effects of digoxin, digitoxin, and oleander poisoning. These antibodies are useful in the treatment of acute and chronic digitalis intoxication in all age groups, including geriatric and pediatric populations. Digoxin-specific Fab antibodies have a high degree of specificity to digoxin, and their administration causes rapid lowering of free serum digoxin to minuscule levels. Allergic reactions to digoxin-specific Fab antibodies are infrequent. The benefit of these antibodies has been demonstrated in numerous case reports and clinical trials. A review of 150 cases compiled over a 13-year period found approximately 80% of patients suffering from advanced digitalis intoxication responded completely to treatment with Fab fragments; another 10% improved substantially. This article will review the current scientific reasoning concerning the diagnosis and management of digitalis intoxication and the expanding role of digoxin-specific Fab antibodies. (Am J Emerg Med 1991;9:29-32 [suppl 11. Copyright Co 1991 by W.B. Saunders Company) The foxglove when given in very large and repeated doses occasions sickness, vomiting, purging. giddiness, confused vision. objects appearing green or yellow: increased secretion of urine, with frequent motions to part with it. and sometime inability to retain it; slow pulse, even as slow as 35 beats in a minute. cold sweats. convulsions, syncope. death.’ Since 1785. when William Withering tirst described the adverse effects of foxglove. the plant from which digitalis is derived.
From the Department of Medicine, UCLA School of Medicine, Department of Emergency Medicine, Olive View/UCLA Medical Center, Los Angeles Poison Center, Los Angeles, CA. Address reprint requests to Dr Bayer, 14445 Olive View Drive, Sylmar, CA 97342. Key Words: Digitalis intoxication, digoxin-specific Fab antibodies, Fab antibodies. Copyright (P 1991 by W.B. Saunders Company 0735-6757/91/0902-1007$5.00/O
physicians have been repeatedly called on to treat patients suffering from digitalis intoxication. Digoxin’s wide use. coupled with its inherent toxicity. make this drug one of the more common candidates for serious accidental and deliberate overdose, both chronic and acute. Currently, digoxin is the I lth most frequently prescribed medication in office practice in the United States.’ Estimates of toxicity in digitalized patients vary from 6% to 23%, with specific signs and symptoms depending on the general health of the patient and on whether the toxicity is acute or chronic.3-b Most often. toxicity occurs in patients on longterm cardiac glycosides: however, there are numerous reports of acute overdose in healthy patients.7.8 Fatalities occur in all age groups. In the past. treatment of digitalis intoxication has been hindered by difficulties in diagnosis as well as the lack of a specific antagonist to reverse life-threatening complications. Better recognition of the subtle manifestations of digitalis poisoning will lead to more prompt institution of therapy. Today, the therapeutic arsenal designed to combat digitalis intoxication has been boosted considerably by the addition of digoxin-specific Fab antibodies. The results of a I3-year multicenter trial involving 150 patients treated with Fab antibodies for life-threatening digitalis intoxications demonstrate the usefulness of this new antidote.’ This study and others presented in this supplement detail a comprehensive and current overview on the recognition and management of digitalis intoxications. The highlights of this information and its implications for emergency medicine specialists are provided in this article. RECOGNITION
OF DIGITALIS
INTOXICATION
The diagnosis of digitalis intoxication can be difficult for several reasons: (I ) the associated signs and symptoms are often subtle and nonspecific; (2) electrocardiographic (ECG) findings of cardiac manifestations are often nonspecific: (3) serum digoxin concentrations do not always correlate with toxicity. Each of these factors are discussed in more detail below. Signs and Symptoms The signs and symptoms of digitalis intoxication can be separated into cardiac and extracardiac manifestations. There are a multitude of extracardiac manifestations associated with excess digitalis that are nonspecific and can be confused with other disease states. Most of these symptoms are related to the central nervous system and gastrointestinal tract. The incidence of such symptoms is difficult to quantify, but as a result of a pharmaceutical formulation error in 1970 in the Netherlands, researchers were able to identify the most common symptoms of digitalis intoxication.” One hundred seventy-nine patients developed digitalis toxicity from receiving tablets that contained 0.2 mg of digitoxin as well as 0.05 mg of digoxin instead of the intended 0.25 mg of digoxin. The two most common symptoms reported 29
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were fatigue (95%) and visual symptoms (95%) such as seeing halos of light or enhanced perception of yellow and green colors. Other common symptoms reported were weakness (82%), nausea (8 1%). and anorexia (80%). Gastrointestinal symptoms are frequent in both acute and chronic digitalis toxicity. Anorexia, nausea, and vomiting have an incidence ranging from 30% to 80%.4,‘o,’’ Anorexia can occur relatively early in digitalis intoxication, often preceding nausea and vomiting.‘* Gastrointestinal symptoms usually present early in the course of an overdose and are thought to be centrally mediated, as they are seen with both intravenous and oral preparations.13 Gastrointestinal symptoms appear to occur with the same frequency in all age groups. Wofford and Ettinger, in an evaluation of the Digibind@ Postmarketing Surveillance Study, suggested that in cases of life-threatening toxicity, there is no age-related difference in the incidence of nausea and vomiting.14 In elderly patients in particular, it can be difficult to distinguish the gastrointestinal symptoms of digitalis toxicity from those caused by other medical conditions. Neurological and visual manifestations occur in both acute and chronic toxicity. “J Neurological signs and symptoms range from malaise, headache, fatigue, depression, or confusion to hallucinations and delirium. Visual disturbances present as blurring and alterations in color and pattern vision.16 Most of the neurological manifestations of digitalis intoxication are nonspecific and can mimic other disease entities. Toxic neuropsychiatric manifestations of digoxin can occur at therapeutic concentrations rendering the diagnosis even more difficult.17 Both neurological and visual manifestations may persist after other signs of toxicity have resolved.6 Cardiac manifestations are the life-threatening complications of digitalis intoxication. Arrhythmias can be due to depression or blockade of conduction and/ or enhanced impulse formation. Enhanced impulse formation may appear in the form of atrial, junctional, or ventricular arrhythmias. Disturbances of conduction can occur in the sinus and atrioventricular node. Interference with sinus node conduction takes the form of sinus bradycardia, sinus arrest or sinoatrial block. Significant depression of conduction at the atrioventricular (AV) node can present as second- and third-degree AV block. Second-degree block usually manifests as Wenkebach; Mobitz II is uncommon in digitalis toxicity. Early toxicity may present with prolongation of the PR interval.” Atria1 tachycardia with heart block is caused by both disturbances in conduction and enhanced impulse formation.14 In an otherwise healthy patient suffering from an acute overdose, ventricular arrhythmias or ectopy are uncommon.‘5.‘9 The healthy myocardium often responds to digitalis excess with the development of AV conduction disturbances.” Conversely, the diseased heart frequently responds with ectopic impulse formation particularly from ventricular foci.” Digitalis excess can cause a wide variety of arrhythmias. Rhythms less likely to be caused by digitalis intoxication include atria1 fibrillation with a rapid irregular ventricular response and wide complex regular ventricular tachycardia.” Although bradyarrhythmias are not specific for digitalis excess, certain tachyarrhythmias are characteristic of digoxin intoxication. These include atria1 tachycardia with variable AV block, accelerated junctional rhythms (especially in the setting of atria1 fibrillation), and fascicular tachycardia.*’ Acute digoxin overdoses result in hyperkalemia as a result of poisoning of the membrane-bound sodium potassium pump.
MEDICINE
n Volume 9, Number 2 (Supplement 1) W March 1991
This selective poisoning results in increased extracellular and decreased intracellular potassium, thus reducing the normal resting membrane potential. Consequently, the myocardial cells lose their ability to function as pacer cells, and blocks or asystole result.*’ The degree of hyperkalemia in acute digitalis overdoses may have some predictive value of patient outcome. Gaultier and Bismuth reported a mortality rate of 35% for digitalis intoxicated patients who had a potassium greater than 5 mEq/L and who were treated by conventional means.” However, in chronic toxicity, the potassium is usually normal or low. Potassium can be depleted by diuretics, which are prescribed along with digoxin for the treatment of heart failure. Hypokalemia increases the binding of digoxin to myocardial receptors and is a predisposing factor in the development of digitalis toxicity.‘4 Other conditions predisposing to digitalis intoxication include hypomagnesemia, advanced heart disease, chronic pulmonary disease, and concomitant drug administration such as quinidine and verapamil.20.23
Serum Digoxin Concentration levels Most clinical laboratories use a radioimmunoassay (RIA) technique to measure serum digoxin concentration levels. The development of radioimmunoassay to quantitate serum concentrations of digoxin or digitoxin accurately and reproducibly has been an important step in the improved capability to diagnoses digitalis intoxication. 24 However, there are limitations in correlating serum digoxin concentration levels with clinical toxicity. Most studies have demonstrated considerable overlap of serum digoxin levels between groups with and without toxicity.24 The time that the test was drawn in relation to when the overdose occurred is important. Serum digoxin levels obtained soon after an overdose may not accurately reflect toxicity, as the drug may still be in the distribution place. There are a number of variables that may affect the sensitivity of individual patients to digitalis. Pediatric patients appear to be more resistant to the cardiotoxic effects of digoxin than adults at comparable levels.25 Springer et al reported an 1&month-old child who after a massive digoxin overdose had a serum digoxin level of 48 ng/mL. This child developed only mild manifestations of digitalis toxicity.26 Alternately, patients with advanced myocardial disease, electrolyte imbalances, or hypothyroidism may be more sensitive to digitalis and develop toxicity at “normal” ranges of serum digoxin concentration levels. Finally there are endogenous digoxinlike substances (EDLS) that have been reported to cause false-positive digoxin values in newborns, pregnant women, and adults with kidney and liver disease.27.28 Thus, the physician must use clinical judgement in assessing patients with possible digitalis intoxications; no single laboratory value should be solely relied on to make a diagnosis.
MANAGEMENT OF OIGITALIS INTOXICATION Prior to the use of digoxin-specific Fab antibodies, treatment of digitalis intoxication was largely supportive. Currently, supportive measures remain the cornerstone of therapy. Once the patient has been stabilized, the usual modalities for gastric decontamination (ipecac, lavage, charcoal, cathartic) are used for acute overdose. Because both emesis and lavage may increase vagal tone thereby worsening AV block or bradycardia, pretreatment with atropine has been recommended.6 Multiple dose charcoal has been recommended for digitoxin, which undergoes significant enterohepatic recirculation, as well as for digoxin.29
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However, the clinical effectiveness of serial charcoal in the treatment of digitalis intoxication has not been established. Procedures designed to enhance elimination such as forced diuresis, hemodialysis, and hemoperfusion are of limited usefulness due to digoxin’s high volume of distribution. Conventional treatment of severe hyperkalemia in acute overdose patients consists of administering glucose, insulin, and bicarbonate to force potassium into the intracellular space. The management of arrhythmias is directed toward the cause of the rhythm disturbance. Disturbances of impulse conduction with bradycardia compromising hemodynamic stability are treated with atropine and, if necessary, a pacemaker. Phenytoin and lidocaine are the agents of choice in managing arrhythmias characterized by enhanced automaticity (ventricular premature beats, ventricular tachycardia). Phenytoin is also effective in converting atria1 tachycardia with block to sinus rhythm. Phenytoin is particularly useful as an antiarrhythmic for digitalis intoxication because it enhances depressed AV nodal conduction. Quinidine and procainamide (type I, antiarrhythmics) should not be used as they can severely depress conduction in the SA node, AV node, and His-Purkinje tract and consequently can worsen digitalis-induced arrhythmias.” Therapy for digitalis intoxication has advanced significantly with the introduction of a specific antidote to reverse life-threatening complications. Digoxin-specific Fab antibodies, first used to reverse human poisoning in 1976.30 have proven to be safe and markedly effective. A recently concluded multicenter trial of 150 patients with life-threatening digitalis intoxication treated with Fab antibodies provided conclusive evidence of their efficacy and safety.’ The patients, suffering from both acute and chronic overdoses, ranged in age from I day to 94 years old. The intoxications were severe. The median ingested dose of digoxin in acute overdoses was 12.5 mg. The median serum digoxin level was 8.0 ng/mL. Life-threatening complications included refractory ventricular tachycardia (46%). ventricular fibrillation (33%). high-grade AV block (53%). and hyperkalemia (37%). Treatment with digoxin specific antibodies resulted in striking improvement in most patients. Eighty percent of the patients had complete resolution of their intoxication, and 10% demonstrated improvement of their signs and symptoms. Most dramatic were the number of patients who were successfully resuscitated from cardiac arrest. Thirty of 56 patients (54%) whose digitalis toxicity led to cardiac arrest survived hospitalization. This survival rate using Fab antibodies compares favorably to the 100% mortality of digitalis induced cardiac arrest when patients were treated with conventional therapy alone. 3’ An observational surveillance study of an additional 7 17 digitalis intoxicated patients treated with Fab antibodies demonstrated that 74% of patients had a complete or partial response to the antibodies.3” There were no allergic responses in the multicenter trial and 6 cases ofan allergic skin rash in the observational surveillance study. Allergic manifestations occurred in less than 1% of patients. Other adverse events related to Fab included hypokalemia, worsening of congestive heart failure, and increased ventricular rate of patients with atrial fibrillation. These phenomena occurred in less than lW% of patients?’ Based on the evidence to date, digoxin-specific Fab antibodies are safe and effective. Prior to the conclusion of studies confirming their safety and efficacy. Fab antibodies were recommended for use in digitalis intoxication with potentially life-threatening arrhythmias and/or hyperkalemia after standard therapy had
failed. Clearly. these earlier guidelines need revision. Digoxinspecific Fab antibodies should be administered as early as possible in the course of a life-threatening digitalis intoxication. Physicians treating this entity should not wait for the failure of conventional therapeutic measures before deciding to use Fab antibodies. This antidote should be promptly given to those patients suffering from digitalis induced ventricular arrhythmias. high-grade AV block, and/or severe hyperkalemia (potassium concentrations greater than 5 mEq/L). Similarly, Fab antibodies should be administered to patients in cardiac arrest suspected of digitalis intoxication. If the dose of digoxin ingested is established as potentially life-threatening (Rumack reports this as greater than 10 mg in a healthy adult and greater than 4 mg in a healthy child33) and signs of cardiac toxicity are apparent, then Fab antibodies should be administered. Digoxin serum concentrations may be of use in predicting severe toxicity and assessing the need for Fab antibodies. Ordog et al in a retrospective review of 5.100 patients on digoxin, reported a mortality rate of 50% in those patients with serum digoxin levels greater than 6 ng/mL.34 Given this high mortality rate, it would be prudent to seriously consider Fab antibodies for those patients with signs of cardiac toxicity and postdistribution serum digoxin levels of greater than 6 ng/mL. The threshold for administering digoxin specific Fab antibodies is lower in infants and the elderly as well as patients with underlying heart or lung disease. It is essential that patients suffering from digitalis intoxications be closely monitored and observed. If Fab antibodies are administered, total serum digoxin concentration levels rise significantly and cannot be used to guide therapy. Potassium levels have to be monitored carefully as Fab can produce hypokalemia. Hypokalemia can become an even more serious problem if treatment measures (such as glucose. insulin, and bicarbonate) have been instituted for hyperkalemia in addition to Fab. Other adverse events with Fab. such as worsening of congestive heart failure or an increase in ventricular rate in patients with atria1 fibrillation, can occur from loss of digitalis effect. In essence, however. the benefits of digoxin-specific Fab antibodies far outweigh the risks. The emergency physician now has a specific antidote that can dramatically reduce the morbidity and mortality associated with the cardiotoxic effects of digitalis. REFERENCES 1. Withering W: An account of the foxglove and some of its medical uses; with practical remarks on dropsy, and other diseases. Facsimile reprint of 1785 ed. Birmingham, AL: The Classics of Medicine Library. Gryphon Editions Ltd, 1979, p 184 2. Sueta C, Carey T, Burnett C: Reassessment of indications for digoxin. Arch Intern Med 1988;149:609-612 3. Smith TW, Harker E: Digitalis. N Engl J Med 1973;289:11251128 4. Belier GA, Smith TW, Abelman WI-I: Digitalis intoxication. A prospective clinical study with serum correlation. N Engl J Med 1971;284:989-996 5. Elkins BR, Wantabe AS: Acute digoxin poisonings. Am J Hosp Pharm 1978;35:268-277 6. Sharff JA, Bayer MJ: Acute and chronic digitalis toxicity: Presentation and treatment. Ann Emerg Med 1982;11:327-331 7. Propp DA, Hogan T, Mattimore J: Nausea, dyspnea, and heart block in an 86-year-old patient with congestive heart failure. Ann Emerg Med 1988;17:261-267 8. Litovitz TH. Schmitz BF. Helm KC: 1988 annual report of the American Association of Poison Control Centers National Data Collection System. Am J Emerg Med 1988;7:495-545
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9. 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-l 752 10. Lely AH, Van Enter CHJ: Large scale digitoxin intoxication. Br Med J 1970;3:737-740 11. Dubnow MH, Burchell B: Comparison of digitalis intoxication in two separate periods. Ann Intern Med 1915;62:956-965 12. Smith TW, Antman EM, Friedman PL, et al. Digitalis glycosides: Ill. Mechanisms and manifestations of toxicity. Prog Cardiovasc Dis 1984;27:21-55 13. Mason DT, Zellis R, Lee G, et al: Digitalis toxicity. Am J Cardiol 1971;27:546-559 14. Wofford JH, Ettinger WH: Risk factors and manifestations of digoxin toxicity in the elderly. Am J Emerg Med 1991;9:1 l-l 5 (suppl 1) 15. Fowler RS, Rath L, Keith JD: Accidental digitalis intoxication in children. J Pediatr 1964;64:188-199 16. Volpe BT, Soave R: Formed visual hallucinations as digitalis toxicity. Ann Intern Med 1979;91:856-866 17. Eisendrath SJ, Sweeney MA: Toxic neuropsychiatric effects of digoxin at therapeutic serum concentrations. Am J Psychiatr 1987;144: 506-507 18. Chuny EK: Digitalis Intoxication. Baltimore, MD, Williams and Wilkins, 1969, pp, 58-68 19. Smith TW, Willerson JT: Suicidal and accidental digoxin ingestion Circulation 1971;44:29-36 20. Marchlinski FE, Hook BG, Callans DJ: Which cardiac disturbances should be treated with digoxin immune Fab antibody? Am J Emerg Med 1991;9:24-28 (suppl 1) 21. Doherty HE: How and when to use the digitalis serum levels. JAMA 1978;239:2594-2596
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22. Gaultier M, Bismuth C: L’intoxication digitalique aigue. La Rev d Practicien 1978;28:4565-4579 23. Smith TW, Haber E: Digitalis intoxication, clinical presentation and serum concentration. J Clin Invest 1969;49:2377-2386 24. Smith TW, Antman EM, Friedman PL, et al: Digitalis glycosides: I. Mechanisms and manifestations of toxicity. Prog Cardiovasc Dis 1984;26:413-441 25. Lewander WJ, Gaudreault P, Einhorn H, et al: Acute pediatric digoxin ingestion: A ten-year experience. Am J Dis Child 1986;140: 770-773 26. Springer M, Olson K, Feaster W: Acute massive digoxin overdose: Survival without use of digitalis-specific antibodies. Am J Emerg Med 1986;4:364-368 27. Graves SW, Brown B, Valdez R: An endogenous digoxin-like substance in patients with renal impairment. Ann Intern Med 1983;99: 604-608 28. Pudek MR, Seccombe DW, Whitefield MF: Digoxin-like immunoreactivity in premature and full-term infants not receiving digoxin therapy. N Engl J Med 1983;308:904-905 29. Boldy DAR, Smart V, Vale JA: Multiple doses of charcoal in digoxin poisoning. Lancet 1985;2:1076-1077 30. Smith TW, Haber E, Yeatman A, et al: Treatment of life-threatening digitalis intoxication with digoxin-specific Fab antibody fragments, N Engl J Med 1982;307:1359-1362 31. Gaultier M, Bismuth C: L’intoxication digitalique aigue. La Rev d Practicien 1978;28:4565-4579 32. Smith TW: Review of clinical experience with digoxin immune fab (ovine). Am J Emerg Med 1991;9:1-6 (suppl 1) 33. Rumack 8: Cardiac glucosides. Poisindex 1990; 65 34. Ordog G, Benaron S, Bhasin V: Serum digoxin levels and mortality in 5,100 patients. Ann Emerg Med 1987;16:32-39
