Acta Med Scand 200: 4 2 3 4 2 5 , 1976
Extreme Digitalis Intoxication Costa Ahlmark From the Department of Medicine, Falu Hospital, Falun, Sweden
ABSTRACT. A case of massive digoxin intoxication is described. The concentration of digoxin in plasma, 15.5 ng/ml, is one of the highest observed in an individual not having heart disease who survived the intoxication. During the first two days there was complete heart block but only moderate hyperkalaemia. The advantage of temporary pacemaker treatment under these conditions is emphasized.
Digitalis overdosage is a frequent complication of digitalis therapy. Several studies (4, 8, 14) have indicated that about 17-20% of all patients treated with digitalis have symptoms of overdosage and the condition is also considered to be associated with an increased mortality. In contrast to this situation, massive digitalis intoxication, whether accidental or with suicidal intent, is rare. The mortality in these situations has been high, 20-25% ( 1 , 5 , 6 , 12, 15). There are, however, few reports of intake of large doses of digoxin by individuals without heart disease in which the concentration of digoxin in plasma is stated. The present communication reports a case of massive overdosage of digoxin leading to very high plasma concentration levels of digoxin and serious conduction disturbances. CASE REPORT A 45-year-old man with pernicious anaemia, who was otherwise healthy and weighed 98 kg, took 17.5 mg digoxin with suicidal intent. On admission to hospital three hours later, he was fully conscious but suffered from nausea, vomiting and dizziness. Physical examination revealed normal results. BP was 170/90 mmHg and pulse rate %/min. An ECG showed sinus rhythm with only slight ST-T segment depression in the left precordial leads. The patient was transferred to the Intensive Care Unit and during the next few hours he had isolated supra-
ventricular ectopic beats and periods of sinus arrest and increased P-Q time. Eight hours after tablet intake complete AV block occurred, with a ventricular rate of 35/min. Repeated doses of 0.5 mg atropine i.v. were without effect and a transvenous pacemaker electrode was therefore placed in the apex of the right ventricle and on-demand pacemaker treatment at 80 beatslmin was started. Pacing was continued for more than 24 hours and the complete block then disappeared. From the fourth day the patient had normal sinus rhythm without conduction disturbances. The ECG tracings showed marked S-T segment depression and T wave inversion during the first week but no ventricular arrhythmias were observed during the whole observation period of 6 days. Electrolyte status was normal apart from moderate hyperkalaemia during the first two days, 5.5 and 5.3 mmol/l, respectively. Serum magnesium was 0.8 mmol/l. Serum creatinine was normal (80 kmol/l) throughout the period of treatment, as were the urinary volume and BP. The digoxin concentration in plasma, determined by radioimmunoassay, 10 hours after intake of digoxin was 15.5 ng/ml. The digoxin concentration was determined at regular intervals (Fig. I). The patient’s general condition was good throughout the period of treatment but he was troubled by nausea, tinnitus and dizziness during the first three days. No visual disturbances OK periods of incoherence occurred. The patient was able to leave the hospital in full physical health I 1 days after admission.
COMMENTS The toxic effects of large doses of digoxin differ considerably between persons with and without heart disease (5). ‘The case described here demonstrates some of the most typical symptoms of severe overdosage of digoxin in a person previously free from heart disease. When a normal heart is exposed to a very high dose of digoxin, it develops AV conduction disturbances with bradycardia and varying AV block and an increased risk of lethal bradyarrhythmias (1, 2, 5, 15). A diseased heart reacts primarily with increased generation of ectopic impulses, Acta Med Scand 200
424
G . Ahlmark
Digor in conc. 20
10
5
1
0,7 I
I
I
I
I
I
I
1
2
3
4
5
6
I
Time ( d a y )
Fig. 1. Digoxin concentration in plasma during the first seven days after intake of 1 7 3 mg digoxin.
above all from the ventricles, leading to various ventricular arrhythmias. Atropine has been reported to abolish this digitalis-induced AV block in certain cases (10, 15). In other cases, as in the present patient, the extravagal effects of digoxin on the conduction system appear to be the main cause of the AV block. Treatment may be difficult in these cases, especially in view of the great risk of lethal bradyarrhythmias in connection with complete block ( I ) . Phenytoin improves conduction in the AV node and has been successfully used in digitalis intoxication (9); it has also given good results in AV block due to massive doses of digoxin (13). Acru Med Scund 200
When AV conduction disturbances occur which cannot be treated successfully with drugs, the patient should be provided with a temporary transvenous pacemaker electrode before malignant bradyarrhythmias arise. In the case reported here complete block occurred nine hours after intake of digoxin. As the block did not respond to atropine, the patient was treated with an on-demand pacemaker for the next 24 hours and no further arrhythmias were observed. No ventricular arrhythmias were seen even during the first 24 hours, when the plasma levels of digoxin were very high. The initial plasma concentration of digoxin, 15.5 nglml, ten hours after intake of digoxin, is one
Eitreme digitalis intoxication of the highest reported in an individual without heart disease who survived the intoxication. The normal half-life in blood for digoxin has been calculated to be about 31 hours (3). After intake of large doses of digoxin, however, the half-life has been substantially shorter (7, 13, IS). Smith and Willerson ( 15) found that the half-life during the first two days was about 10 and 21 hours, respectively, subsequently increasing to normal values. In this case the digoxin concentration fell relatively rapidly, with a calculated approximate half-life during the first two days of about 20 hours. During the following two days the half-life was about 33 hours. By the fourth day the digoxin concentration was less than 2 nglml and no AV conduction disturbances o r other arrhythmias were now present. Massive doses ot' digoxin may cause hyperkalaemia, probably due to a generalized inhibition of cell membrane ATP-ase and consequent altered transport of certain cations, without other electrolyte disturbances or acidosis occurring (1, 2, 6, 11, 12, 15). This hyperkalaemia may be very pronounced and two cases have been reported in which very high doses of digoxin caused refractory hyperkalaemia with lethal outcome (12, IS). In most cases, however, serum potassium becomes normal when the digoxin concentration falls to non-toxic levels. In the case described here, only a moderate hyperkalaemia was observed during the first two days (initially 5.5 mmol/l) despite the very high digoxin concentration. Thus, potassium is contraindicated under these conditions and should not be given until the serum potassium level has been determined and renal function tests have been performed. In cases of moderate digoxin overdosage in individuals with heart disease, on the other hand, potassium must often be given, since hypokalaemia is a frequent finding under these conditions.
425
REFERENCES I . Asplund, J.. Edhag, 0.. Mogensen, L., Nyqvist, E., Orinius, E. & Sjogren, A.: Four cases of massive digitalis poisoning. Acta med. scand. 189: 293, 1971. 2. Bertler, A . , Gustafson, A. & Redfors, A.: Massive
digoxin intoxication. Report of two cases with pharmacokinetic correlations. Acta med. scand. 194: 245, 1973. 3. Doherty, J. E.: The clinical pharmacology of digitalis glykosides: A review. Amer. J. Med. Sci. 255:382, 1%8.
4. Evered, D. C. & Chapman, C.: Plasma digoxin concentrations and digoxin toxicity in hospital patients. Brit. Heart J. 33: 540, 1971. 5. Fowler, R . S . , Rathi, L. & Keith, J. D.: Accidental digitalis intoxication in children. J. Pediat. 64: 188, 1964. 6. Gaultier. M.. FoiJriner. E., Efthymiou, M.-L., Frejaville, J.-P.. Jouannot, P. & Dentan, M.: Intoxication digitalique aigue. Bull. SOC. med. HBp. Paris 119: 247, 1%8. 7. Hobson, J. D. Kr. Zettner, A.: Digoxin serum halflife following suicidal digoxin poisoning. J. Amer. med. Ass. 2: 147, 1973. 8. Jorgensen, A. W. & Sorensen, 0. H.: Digitalis intoxication. Acta med. scand. 188: 179, 1970. 9. Mason, D. T., Zellis, R., Lee, G., Hughes, J. L., Spann, J. F. & Amsterdam, E. A.: Current concepts
and treatment of digitalis toxicity. Amer. J. Cardiol. 27: 546, 1971. 0. Miller, P. H.: Efficacy of atropine in the treatment of digitalis induced 4V block. Dis. Chest 56: 229, 1969. I . Page, E.: The actions of cardiac glycosides on heart muscle cells. Circulation 30: 237, 1964. 2. Reza, J. M., Kovick, B. R., Shine, I. K. & Pearce,
M. L.: Massive intravenous digoxin overdosage. New Engl. J. Med. 291: 777, 1974. 3. Rumack, B. H., Wolfe, R. R. & Gilfrich, H.: Phenytoin (diphenylhydantoin) treatment of massive digoxin overdose. Brit. Heart J. 36: 405, 1974. 1. Shapiro, S . , Slone, D., Lewis, G. P. & Jick, H.: The epidemiology of digoxin. J. chron. Dis. 22: 361, 1969. 15. Smith, T. W. & Willerson, J. T.: Suicidal and accidental digoxin ingestion. Report of five cases with serum digoxin level correlations. Circulation 19: 29, 1971.
Actti
Mrd Sctrnd 200
Extreme Digitalis Intoxication Costa Ahlmark From the Department of Medicine, Falu Hospital, Falun, Sweden
ABSTRACT. A case of massive digoxin intoxication is described. The concentration of digoxin in plasma, 15.5 ng/ml, is one of the highest observed in an individual not having heart disease who survived the intoxication. During the first two days there was complete heart block but only moderate hyperkalaemia. The advantage of temporary pacemaker treatment under these conditions is emphasized.
Digitalis overdosage is a frequent complication of digitalis therapy. Several studies (4, 8, 14) have indicated that about 17-20% of all patients treated with digitalis have symptoms of overdosage and the condition is also considered to be associated with an increased mortality. In contrast to this situation, massive digitalis intoxication, whether accidental or with suicidal intent, is rare. The mortality in these situations has been high, 20-25% ( 1 , 5 , 6 , 12, 15). There are, however, few reports of intake of large doses of digoxin by individuals without heart disease in which the concentration of digoxin in plasma is stated. The present communication reports a case of massive overdosage of digoxin leading to very high plasma concentration levels of digoxin and serious conduction disturbances. CASE REPORT A 45-year-old man with pernicious anaemia, who was otherwise healthy and weighed 98 kg, took 17.5 mg digoxin with suicidal intent. On admission to hospital three hours later, he was fully conscious but suffered from nausea, vomiting and dizziness. Physical examination revealed normal results. BP was 170/90 mmHg and pulse rate %/min. An ECG showed sinus rhythm with only slight ST-T segment depression in the left precordial leads. The patient was transferred to the Intensive Care Unit and during the next few hours he had isolated supra-
ventricular ectopic beats and periods of sinus arrest and increased P-Q time. Eight hours after tablet intake complete AV block occurred, with a ventricular rate of 35/min. Repeated doses of 0.5 mg atropine i.v. were without effect and a transvenous pacemaker electrode was therefore placed in the apex of the right ventricle and on-demand pacemaker treatment at 80 beatslmin was started. Pacing was continued for more than 24 hours and the complete block then disappeared. From the fourth day the patient had normal sinus rhythm without conduction disturbances. The ECG tracings showed marked S-T segment depression and T wave inversion during the first week but no ventricular arrhythmias were observed during the whole observation period of 6 days. Electrolyte status was normal apart from moderate hyperkalaemia during the first two days, 5.5 and 5.3 mmol/l, respectively. Serum magnesium was 0.8 mmol/l. Serum creatinine was normal (80 kmol/l) throughout the period of treatment, as were the urinary volume and BP. The digoxin concentration in plasma, determined by radioimmunoassay, 10 hours after intake of digoxin was 15.5 ng/ml. The digoxin concentration was determined at regular intervals (Fig. I). The patient’s general condition was good throughout the period of treatment but he was troubled by nausea, tinnitus and dizziness during the first three days. No visual disturbances OK periods of incoherence occurred. The patient was able to leave the hospital in full physical health I 1 days after admission.
COMMENTS The toxic effects of large doses of digoxin differ considerably between persons with and without heart disease (5). ‘The case described here demonstrates some of the most typical symptoms of severe overdosage of digoxin in a person previously free from heart disease. When a normal heart is exposed to a very high dose of digoxin, it develops AV conduction disturbances with bradycardia and varying AV block and an increased risk of lethal bradyarrhythmias (1, 2, 5, 15). A diseased heart reacts primarily with increased generation of ectopic impulses, Acta Med Scand 200
424
G . Ahlmark
Digor in conc. 20
10
5
1
0,7 I
I
I
I
I
I
I
1
2
3
4
5
6
I
Time ( d a y )
Fig. 1. Digoxin concentration in plasma during the first seven days after intake of 1 7 3 mg digoxin.
above all from the ventricles, leading to various ventricular arrhythmias. Atropine has been reported to abolish this digitalis-induced AV block in certain cases (10, 15). In other cases, as in the present patient, the extravagal effects of digoxin on the conduction system appear to be the main cause of the AV block. Treatment may be difficult in these cases, especially in view of the great risk of lethal bradyarrhythmias in connection with complete block ( I ) . Phenytoin improves conduction in the AV node and has been successfully used in digitalis intoxication (9); it has also given good results in AV block due to massive doses of digoxin (13). Acru Med Scund 200
When AV conduction disturbances occur which cannot be treated successfully with drugs, the patient should be provided with a temporary transvenous pacemaker electrode before malignant bradyarrhythmias arise. In the case reported here complete block occurred nine hours after intake of digoxin. As the block did not respond to atropine, the patient was treated with an on-demand pacemaker for the next 24 hours and no further arrhythmias were observed. No ventricular arrhythmias were seen even during the first 24 hours, when the plasma levels of digoxin were very high. The initial plasma concentration of digoxin, 15.5 nglml, ten hours after intake of digoxin, is one
Eitreme digitalis intoxication of the highest reported in an individual without heart disease who survived the intoxication. The normal half-life in blood for digoxin has been calculated to be about 31 hours (3). After intake of large doses of digoxin, however, the half-life has been substantially shorter (7, 13, IS). Smith and Willerson ( 15) found that the half-life during the first two days was about 10 and 21 hours, respectively, subsequently increasing to normal values. In this case the digoxin concentration fell relatively rapidly, with a calculated approximate half-life during the first two days of about 20 hours. During the following two days the half-life was about 33 hours. By the fourth day the digoxin concentration was less than 2 nglml and no AV conduction disturbances o r other arrhythmias were now present. Massive doses ot' digoxin may cause hyperkalaemia, probably due to a generalized inhibition of cell membrane ATP-ase and consequent altered transport of certain cations, without other electrolyte disturbances or acidosis occurring (1, 2, 6, 11, 12, 15). This hyperkalaemia may be very pronounced and two cases have been reported in which very high doses of digoxin caused refractory hyperkalaemia with lethal outcome (12, IS). In most cases, however, serum potassium becomes normal when the digoxin concentration falls to non-toxic levels. In the case described here, only a moderate hyperkalaemia was observed during the first two days (initially 5.5 mmol/l) despite the very high digoxin concentration. Thus, potassium is contraindicated under these conditions and should not be given until the serum potassium level has been determined and renal function tests have been performed. In cases of moderate digoxin overdosage in individuals with heart disease, on the other hand, potassium must often be given, since hypokalaemia is a frequent finding under these conditions.
425
REFERENCES I . Asplund, J.. Edhag, 0.. Mogensen, L., Nyqvist, E., Orinius, E. & Sjogren, A.: Four cases of massive digitalis poisoning. Acta med. scand. 189: 293, 1971. 2. Bertler, A . , Gustafson, A. & Redfors, A.: Massive
digoxin intoxication. Report of two cases with pharmacokinetic correlations. Acta med. scand. 194: 245, 1973. 3. Doherty, J. E.: The clinical pharmacology of digitalis glykosides: A review. Amer. J. Med. Sci. 255:382, 1%8.
4. Evered, D. C. & Chapman, C.: Plasma digoxin concentrations and digoxin toxicity in hospital patients. Brit. Heart J. 33: 540, 1971. 5. Fowler, R . S . , Rathi, L. & Keith, J. D.: Accidental digitalis intoxication in children. J. Pediat. 64: 188, 1964. 6. Gaultier. M.. FoiJriner. E., Efthymiou, M.-L., Frejaville, J.-P.. Jouannot, P. & Dentan, M.: Intoxication digitalique aigue. Bull. SOC. med. HBp. Paris 119: 247, 1%8. 7. Hobson, J. D. Kr. Zettner, A.: Digoxin serum halflife following suicidal digoxin poisoning. J. Amer. med. Ass. 2: 147, 1973. 8. Jorgensen, A. W. & Sorensen, 0. H.: Digitalis intoxication. Acta med. scand. 188: 179, 1970. 9. Mason, D. T., Zellis, R., Lee, G., Hughes, J. L., Spann, J. F. & Amsterdam, E. A.: Current concepts
and treatment of digitalis toxicity. Amer. J. Cardiol. 27: 546, 1971. 0. Miller, P. H.: Efficacy of atropine in the treatment of digitalis induced 4V block. Dis. Chest 56: 229, 1969. I . Page, E.: The actions of cardiac glycosides on heart muscle cells. Circulation 30: 237, 1964. 2. Reza, J. M., Kovick, B. R., Shine, I. K. & Pearce,
M. L.: Massive intravenous digoxin overdosage. New Engl. J. Med. 291: 777, 1974. 3. Rumack, B. H., Wolfe, R. R. & Gilfrich, H.: Phenytoin (diphenylhydantoin) treatment of massive digoxin overdose. Brit. Heart J. 36: 405, 1974. 1. Shapiro, S . , Slone, D., Lewis, G. P. & Jick, H.: The epidemiology of digoxin. J. chron. Dis. 22: 361, 1969. 15. Smith, T. W. & Willerson, J. T.: Suicidal and accidental digoxin ingestion. Report of five cases with serum digoxin level correlations. Circulation 19: 29, 1971.
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Mrd Sctrnd 200
