- Email: [email protected]
Acute digitalis poisoning: The role of intravenous magnesium sulfate
The Joumai of Emergency
Medlone,
Vol 4, pp 463-469.
1986
Printed in the USA
l
CopyrIght
ACUTE DIGITALIS POISONING: THE ROLE OF INTRAVENOUS MAGNESIUM Earl J. Reisdorff, Michigan
Reprint
address:
MD,
Michael R. Clark,
digoxin;
poisoning;
Introduction Acute digoxin poisoning is a challenging problem for the emergency medicine specialist. Cardiac glycoside poisoning, from either suicide attempt or accidental ingestion, differs markedly from chronic digitalis toxicity in both clinical presentation and treatment. Early diagnosis and intervention is essential. In digitalis poisoning, magnesium sulfate can be an effective pharmacologic intervention. In 1935
B B RECEIVED:
FACEP,
Journals
Ltd
SULFATE
and Bradford L. Walters,
State University, Affiliated Emergency Medicine Residency, Edward Sparrow Hospital and lngham Medical Center E. Reisdorff, MD, Sparrow Hospital, 1215 E Michigan, Lansing,
Cl Abstract -Acute digitalis poisoning is a complex emergency with a reported mortality rate of 3% to 2Wo.’ In severe overdose, the sodium, potassium-adenosine triphosphatase system is severely inhibited, leading to cardiac dysrhythmias and an elevation of the serum potassium. Magnesium, a cofactor regulating this ion transport system, can successfully treat acute digitalis-induced rhythm disturbances and restore the transmembrane potassium gradient. This paper discusses the cellular mechanism involved in digitalis toxicity and reviews the literature concerning the use of magnesium in acute cardiac glycoside poisoning. 0 Keywordsdigitalis; magnesium; toxicology
MD,
0 1986 Pergamon
MD
MI 48909
Zwillinger reported the use of magnesium sulfate to treat digitalis dysrhythmias.2 Recent case studies and research support magnesium’s efficacy in this life-threatening condition.
Pharmacology
and Mechanism
In adults, gastrointestinal absorption is 60% to 80% of the ingested dose for digoxin and essentially 100% for digitoxin.’ Digoxin is excreted unchanged by the kidneys. Digitoxin is metabolized by the liver, with a significant enterohepatic circulation.“x5 The half-life for digoxin and digitoxin differ, being 1.5 days and 4 to 6 days, respectively.6 For digoxin, the halflife is variable in acute overdose, ‘ml4with some reports describing a biphasic elimination with an initially shortened half-life than a normal or prolonged elimination phase.l1-14 Digitalis exerts a positive inotropic effect on the myocardium. The mechanism proposed by Wilbrandt is that of cardiac glycoside inhibition of the sodium, potassium-adenosine triphosphatase (Na,KATPase) system, which raises the intracellular calcium concentration.” This
Toxicology-one of the most critical and challenging areas confronting the emergency department staff-is coordinated by Kenneth Kulig, MD, of the Rocky Mountain Poison Center.
28 January 1986; ACCEPTED:
19 August 1986 463
0736-4679/86 $3.00 + .OO
464
Table 1. Prominent
E. J. Reisdorff, M. Ft. Clark, and B. L. Walters
Differences
Findings
Between Chronic Digoxin Toxicity and Acute Digoxin Poisoning
Chronic Digoxin Toxicity
Acute Digoxin Poisoning
Noncardiac symptoms
A wide range of gastrointestinal, ocular, CNS, and nonspecific manifestations are commonly present.
Nausea and vomiting are common; other classic symptoms are not reported with consistency.
Cardiac symptoms
Premature ventricular contractions are the most common dysrhythmias; atrial tachycardias, sometimes associated with block, also are seen.
Ventricular dysrhythmias are not common; supraventricular dysrhythmias with heart block are the most characteristic findings; bradycardia is often reported.
Serum potassium on admission
Generally low serum K+ secondary concomitant diuretic therapy.
Normal to elevated serum potassium depending on the degree of Na + , K + ATPase pump inhibition.
Serum digoxin values
Variable but can be within the therapeutic range.
High levels are always seen in patients with symptoms of toxicity.
Serum half-life of digoxin
Reasonably constant in adults and children; close to the same for both groups.
Reported to be shortened in acute poisoning although this has not been consistent.
Reproduced with permission 1976; 35266-77.
of Ekins BR, Watanabe
to
AS: Acute digoxin
increased availability of calcium enhances myocardial contractility. Further studies have shown that the normal efflux of calcium from the myocardial cell is interrupted when the transmembrane sodium gradient is decreased by the Na,K-ATPase inhibition. The subsequent rise in intracellular calcium allows an increase in the number of actin-myosin interactions. In a study by Skou, the myocardial Na,K-ATPase system, which facilitates the efflux of intracellular calcium, was shown to require magnesium as a cofactor.‘6 It is this magnesium-ATPase relationship that forms the pharmacologic basis for using intravenous magnesium in the treatment of digitalis poisoning.
Review of the Literature A review of 35 reports involving 235 cases of massive digitalis ingestions (both suicidal and accidental) revealed 48 deaths, for an overall reported mortality of 20.4V0’-‘~, L7-43.Among children, the mortality was 12.7%, with digoxin being ingested by 8 1% and digitoxin by 8%. There is no statistical relationship between mortal-
poisoning.
Review
of therapy.
Am JHosp
Pharm
ity and the type of digitalis preparation taken. The mortality in adults was 30.39’0, with digoxin taken in 86% of the cases and digitoxin in 6%. When digitalis preparations other than digoxin were ingested, the mortality reached 7 1%. A mortality of 80% was seen in those patients with a digoxin level greater than 25 ng/mL. Of these 35 reports and reviews, only six discuss the use of magnesium in digitalis overdose.7~13~35~36~40 This information emphasizes the potential lethality of digitalis overdose and the need for prompt effective treatment.
Clinical Presentation The effects of acute digitalis overdose differ from those of chronic toxicity (Table l).M The acutely poisoned population tends to be younger and free of ischemic heart disease compared with the older population at risk for chronic toxicity. Hence, they are better able to withstand the toxic insult and are less prone to developing dysrhythmias. Also, in acute digitalis overdose, there are rapid shifts of Na+ and K+ across the myocardial
465
Acute Digitalis Poisoning
Table 2. Common Signs Acute Digitalis Poisoning
and Symptoms
of
CNS: Drowsiness, lethargy, confusion, disorientation, headache, visual disturbances Cardiovascular: Almost any dysrhythmia; most commonly bradycardia and conduction disturbances Gastrointestinal: Nausea, vomiting, abdominal pain, anorexia Electrolytes: Hypokalemia, hyperkalemia
membrane not seen in chronic toxicity, leading to severe electrolyte disturbances. Nausea and vomiting frequently are the first symptoms of digitalis toxicity (Table 2). Diarrhea and abdominal pain may also occur, Mental status changes, such as drowsiness, disorientation, and lethargy are commonly seen. Severe CNS involvement includes agitation and occasionally seizures.23*25B35Photophobia, scotomata, and xanthopsia (yellow vision) are described in chronic toxicity, but are uncommon in acute digitalis poisoning.45-47 Electrolyte disturbances are frequent in massive ingestions. While hypokalemia from diuretic use is associated with chronic toxicity, life-threatening hyperkalemia occurs in acute poisoning.‘4a34*“,4*,49 The acute inhibition of the Na,K-ATPase system can result in a decreased cellular influx of potassium and a consequent rise in serum potassium.6.48 The subsequent change in the membrane potential depresses the myocardial conduction system resulting in conduction delays. These atrioventricular (AV) conduction problems seen in acute digitalis poisoning are exacerbated by a digitalis-induced increase in vagal tone. The rhythm can slow and complete AV dissociation may develop. Ventricular tachycardia and fibrillation, when they occur, are often refractory to resuscitative measures.
Magnesium
and Digitalis
A number of pharmacologic approches to digitalis poisoning have been reported. Magnesium sulfate has stood out as being
efficacious in acute digitalis overdose. Hypomagnesemia is a predisposing and exacerbating factor in digitalis toxicity. Individuals with digitalis toxicity are found to have a higher incidence of hypomagnesemia.s”-54 Vitale found that puppies fed magnesium deficient diets were more sensitive to the toxic effects of digitalis.” As the dogs become hypomagnesemic, they were more prone to develop ventricular tachycardia at lower cardiac glycoside levels. Similar results were found with simians.‘h Another canine study demonstrated that hypomagnesemia prolonged electrocardiographic changes and toxic effects caused by digitalis.57 When hypomagnesemia was achieved by hemodialysis, the amount of cardiac glycoside needed to induce dysrhythmia was significantly lowered.5XIn dogs with digitoxic dysrhythmias, intravenous magnesium sulfate promptly restored a sinus rhythm in 75% of cases. The first reported human use of magnesium to treat digitalis-induced dysrhythmias was by Zwillinger in 1935 .I He used an intracardiac injection of magnesium to control an episode of ventricular tachycardia due to digitalis toxicity. Later, Boyd and Scherf described treating digitalis-induced paroxysmal tachycardias with magnesium. 59 Subsequent reports have continued to show the effectiveness of magnesium in treating digitoxic dysrhythmias.S’-h’
Treatment
of Digitalis
Poisoning
As with any poisoning, identifying the offending agent, removing or neutralizing the toxin, and administering antidotal therapy is axiomatic. Ipecac-induced emesis is recommended in the noncomatose patient, but great caution should be exercised.44,63-66 The vagal stimulation from vomiting may induce or worsen an AV block. If a conduction disturbance is seen, atropine (0.5-l .O mg) should be given intravenously (IV) prior to the administration of ipecac. This can also be done before giving ipecac in the patient with a
466 normal sinus rhythm to prevent the precipitation of bradycardia or a conduction disturbance. Activated charcoal is also recommended because it inhibits the gastrointestinal absorption of digoxin.67 Repeated charcoal dosing may be efficacious with both digoxin and digitoxin. Cathartics containing magnesium salts can be administered, but any additional benefit of the magnesium ion in this setting is speculative. An equally effective cathartic is D-sorbitol. All digitalis ingestions require continuous cardiac monitoring until the patient shows no clinical or ECG signs of toxicity. Initial laboratory studies should include serum potassium, magnesium, calcium, creatinine, and digoxin levels. The serum potassium should be frequently assessed in the early phase of treatment because severe derangements are common and occur rapidly. Serum digoxin levels may have some predictive value. A review of 235 cases of massive digitalis ingestions shows that if the value remains below 2.0 rig/ml, the mortality is 10w.‘-~~J’-~~ Because hyperkalemia may rapidly develop, replacement of potassium should be undertaken with caution in the hypokalemic patient. With Na,K-ATPase inhibition, there is an apparent efflux of potassium from the myocardial cells, allowing potassium to accumulate quickly. Magnesium has a beneficial influence should hyperkalemia occur. Neff showed that the digitalis-induced egress of potassium from the myocardium is halted when magnesium sulfate is administered.@ This may be due to the restorative effect of magnesium on the Na, K-ATPase system,@ but Specter proposes that magnesium sulfate directly influences transmembrane shifts of potassium which would bypass the Na, KATPase system.68 Hyperkalemia can be treated with calcium-binding resins. Calcium should not be used to treat digitalisinduced hyperkalemia because calcium may exacerbate digitalis toxicity. The efficacy of routine electrical pacing is questionable. One report advocates
E. J. Reisdorff, M. R. Clark, and B. L. Walters
prophylactic placement of a venticular pacemaker.36 Since cardiac glycosides lower the threshold for pacemaker-induced extrasystole, placement can potentially produce life-threatening dysrhythmias.6g,70 Such dysrhythmias can be particularly difficult to treat. The added myocardial irritability due to digitalis poisoning can result in refractory ventricular fibrillation upon cardioversion.” For digitalis-induced ventricular dysrhythmias, diphenylhydantoin is the agent of choice. It suppresses the tachydysrhythmias without compromising intraventricular conduction.7,72-74 Atrioventricular conduction may even be restored by phenytoin.75 Lidocaine can also be beneficial in treating dysrhythmias in digitalis poisoning. It can suppress ventricular ectopy without influencing AV conduction. Propranolol, quinidine, and procainamide are of limited value. Bretylium is contraindicated because it may worsen preexisting ventricular tachydysrhythmias or precipitate ventricular fibrillation.76s77 As described above, intravenous magnesium is also an effective agent in treating dysrhythmias from digitalis poisoning. In a report of massive digoxin overdose in which ventricular ectopy was refractory to lidocaine and phenytoin, an infusion of magnesium corrected the rhythm disturbance immediately.22 The adult dose of magnesium in treating digitalis toxicity is 2 g of 10% magnesium sulfate given intravenously over 20 minutes. Magnesium sulfate is prepared as a 50% solution for intramuscular use, so it must be appropriately diluted. The effect of a single bolus injection may be short-lived owing to a rapid renal clearance. This may necessitate a continuous infusion of 1 to 2 g/h. If the serum creatinine level is elevated, one must check the serum magnesium level after the initial bolus prior to starting a continuous infusion. A magnesium level should be checked every two hours, with the dose titrated to maintain a serum level of 4 to 5 mEq/L. Deep-tendon reflexes
Acute Dlgltahs Poisonmg
467
and respiratory depression serve as clinical parameters in assessing the magnesium level. If the reflexes or respiratory pattern become depressed, the magnesium infusion should be halted and the level rechecked. When the serum magnesium concentration is too high, neuromuscular paralysis may ensue. When the victim has normal renal function and the deeptendon reflexes are closely monitored, risks from intravenous magnesium are minimal. The reported use of magnesium in children with digitalis overdose is limited and dosage regimens have not been established. For other disorders, the neonatal magnesium dose is 20 mg/kg intramuscularly (IM) or IV over 20 minutes.78.79 Close monitoring for CNS or respiratory depression is imperative and serum levels should be checked frequently, as in adults.
Digoxin specific Fab antibody fragments show great promise in the treatment of digitalis overdose.30a32s33 Until they are more readily available, magnesium may prove to be an effective temporizing measure.
Summary In conclusion, magnesium is an effective adjunct in the treatment of massive digoxin poisoning. A 3% to 25% mortality rate is associated with this emergency. Intravenous magnesium is a safe, effective pharmacologic intervention, proven to be useful in suppressing digitalis-induced dysrhythmias. Until more definitive therapy is available, magnesium is a useful, potentially life-saving agent in the acute management of digitalis poisoning.
REFERENCES I. Goodman LS: Digitalis in Haddad, LM, Winchester JF (eds): Clinical Management of Poisoning and Drug Overdose, Philadelphia, WB Saunders, 1983, p. 813. 2. Zwillinger L: Uber die Magnesiumwirkung auf das Herz. K/in Wochenschr 1935; 14:1429-1433. 3. Lisalo E: The clinical pharmacokinetics of digoxin. Clin Pharmacokinet 1977; 2:1-16. 4. Doherty JE, DeSoyza N, Kane JJ. et al: Clinical pharmakinetics of digitalis glycosides. Prog Cardiovasc Dis 1978; 21:141-58. 5. Storstein L: Studies on digitalis III: Biliary excretion and enterohepatic circulation of digitoxin and its cardioactive metabolites. Clin Pharmacol Ther 1975; 17:313-20. 6. Smith TW: Digitalis glycosides, N Eng/ J Med 1973; 288:719-722. 7. Rumack RH, Wolfe RR, Gilfrich H: Phenytoin (diphenylhydantoin) treatment of massive digoxin overdose. Br Heart J 1974; 36:405-408. 8. Pearce G, Buchanan N, Uther J: Massive digoxin ingestion in a child. Med / Aust Sept 1980; 279-80. 9. Fresard F, Balant L, Noble J, et al: Cholystryramine et intoxication a la digoxine: Efficacite therapeutique? Schweiz. Med Wochenschr 1979; 109:431-436. IO. Hobson JD, Zettner A: Digoxin serum half-life following suicidal digoxin poisoning. JAMA 1973; 233:147-149. Il. Bertler A, Gustafson A, Redors A: Massive digoxin intoxication: Report of two cases with pharmacokinetic correlations. Acta Med Stand 1973; 194:245-249.
12. Stopfkuchen H, Gilfrich HJ, Jungst BK, et al: Massive digoxin intoxication in childhood. Intensive Care Med 1978; 4: 199-201. 13. Ng RH, Stempsey W, Statland BE: Biphasic profile in the elimination of digoxin from serum after a massive overdose (letter). C/in Chem 1983; 29~393-394. 14. Smith TW, Willerson JT: Suicidal and accidental digoxin ingestion: Report of five cases with serum digoxin level correlations. Circulation 1971; 44:29-36. 15. Wilbrandt W: Zum Wirkingmechanisms des Herzglycosides. Schweiz Med Wochenschr 1955; 85:315-320. 16. Skou JC: The influence of some cations on an adenosine triphosaphate from peripheral nerves. Biochem Biophys Acta 1957; 23:394-401. 17. Holt DW, Trail1 TA, Brown CB: The treatment of digoxin overdose. Clin Nephrol 1975; 3: 119-122. 18. Steentoft A: Fatal digitalis poisoning. Acfa Phar-
macol Toxicol1973; 321353-357. 19. Duke M: Atrioventricular block due to accidental digoxin ingestion treated with atropine. Am
J
Dis Child 1972; 1241745-756. 20. Navab F, Honey M: Self-poisoning with digoxin: Successful treatment with atropine. Br Med J 1967; 3:660-661. 21. Buchanan J: Self-poisoning with digitalis glycosides. BrMed J 1967; 3:661-662. 22. French JH, Thomas RG, Siskind AP et al: Magnesium therapy in massive digoxin intoxication. Ann Emerg Med 1984; 13:562-566. 23. Asplund J, Edhag 0, Mogensen L, et al: Four
468 cases of massive digitalis poisoning. Acta Med &and 1971; 189:293-297. 24. Greenburg M: Accidental digoxin poisoning in a child of 2 years. Arch Dis Child 1957; 32:359-360. 25. Freeman R, Farrar JF, Roberton SEJ: Accidental digitalis poisoning in childhood. Med J Aust Ott 1961:655-659. 26. McNamara DG, Brewer EJ, Ferry GD: Accidental poisoning of children with digitalis. N Engl J Med 1964; 271:1106-l 108. 27. Iisalo E, Nuutila M: Myocardial digoxin concentrations in fatal intoxications. Lancer 1973; 1:257. 28. Nicholls DP: Fatal digoxin overdose. Postgrad Med J 1977; 53:280-281. 29. Maheswaran R, Bramble MG, Hardisty CA: Massive digoxin overdose: Successful treatment with intravenous amiodarone. Br Med J 1983; 287:392-393. 30. Murphy DJ, Bremner WF, Haber E, et al: Massive digoxin poisoning treated with Fab fragments of digoxin-specific antibodies. Pediatrics 1982; 70:472-473. 31. Smiley JW, March NM, Del Guerico ET Hemoperfusion in the management of digoxin toxicity. JAMA 1978; 240~2736-2737. 32. Smith TW, Butler VP, Haber E, et al: Treatment of life-threatening digitalis intoxication with digoxin-specific Fab antibody fragments. N Engl J Med 1982; 307:1357-1357. 33. Rozkovec A, Coltart DJ: Treatment of digoxin overdose with antigen-binding fragments of digoxin-specific antibodies. Br Med J 1982; 285:1315-1316. 34. Reza MJ, Kobick RB, Shine Kl, et al: Massive intravenous digoxin overdosage. N Engl J Med 1974; 291:777-778. 35. Fowler RS, Rathi, L, Keith JD: Accidental digitalis intoxication in children. J Pediatr 1964; 64:188-200. 36. Bismuth C, Motte G. Conso F. et al: Acute diaitoxin intoxication treated by intracardiac pacemaker: Experience in sixty-eight patients. Clin Toxicoll977; 10:433-456. 37. Bergy GC, Fergus EB, Bruce RA: Acute massive digitoxin poisoning: Report of a case and review of the literature. Ann Intern Med 1957; 46:964-976. 38. Bernstein MS, Neschis M, Collini F: Treatment of acute massive digitalis poisoning by administration of a chelating agent. N Engl J Med 1959:261:961-963. 39. Bremner WF, Third JL, Lawrie TDV: Massive digoxin ingestion; Report of a case and review currently available therapies. Br Heart J 1977; 39:688-692. 40. Dyckner T, DeFaire U, Webster PO: Intracellular electrolytes in cardiac and skeletal muscle in fatal digitalis intoxication. Br Heart J 1977; 39:1029-1032. 41. Leeks SR: Suicide by digitalis. NZ Med J 1966; 65:167-168. 42. Citrin D, Stevenson IH, G’Malley K: Massive digoxin overdose: Observations on hyperka-
E. J. Reisdorff, M. R. Clark, and B. L. Walters laemia and plasma digoxin levels. Scott Med J 1972; 17~275-277. 43. Wharton CFP: Attempted suicide by digoxin self administration and its management. G,v Hosp Rep 1970; 119:243-25 1. 44. Ekins BR, Watanabe AS: Acute digoxin poisonings: Review of therapy. Am J Hosp Pharm 1978; 35:268-277. 45. Volpe BT, Soave R: Formed visual hallucinations as digitalis toxicity. Ann Intern Med 1979; 91:865-866. 46. Aronson JK: Digitalis intoxication. Clin Sci 1983; 64:253-258. 47. Lely AH, Van Enter CHJ: Large-scale digitoxin intoxication. Br Med J 1970; 3:737-740. 48. Bismuth C, Gaultier M, Conso F, et al: Hyperkalemia in acute digitalis poisoning: Prognostic significance and therapeutic implications. C/in Toxicoll973; 6:153-162. 49. Goldfrank LR, Kirstein R: Digoxin, in Goldfrank LR (ed): Toxicologic Emergencies: A Comprehensive Handbook in Problem Solving, ed 2. New York, Appleton-Century-Crofts 1982, p. 347-353. 50. Belier GA, Hood WB Jr, Smith TW, et al: Correlation of serum magnesium levels and cardiac digitalis intoxication. Am J Cardiol 1974; 33:225-229. 51. Kim YW, Andrews, CE, Ruth WE: Serum magnesium and cardiac arrhythmias with special reference to digitalis intoxication. Am J Med Sci 1961; 242:87-92. 52. Singh RB, Dube KP, Srivastav PK: Hypomagnesemia in relation to digoxin intoxication in children. Am Heart J 1976; 92:144-147. 53. Cohen L, Kitzes R: Magnesium sulfate and digitalis-toxic arrhythmias. JAMA 1983; 249:2808-2810. 54. Belier GA, Hood WB, Smith TW, et al: Prevalence of hypomagnesemia in a prospective clinical study of digitalis intoxication (abstract). Am J Cardioll970; 26~625. 55. Vitale JJ, Hellerstein EE, Nakamura M, et al: Effects of magnesium-deficient diet upon puppies. Circ Res 1961; 9~387-394. 56. Vitale JJ, Velez H, Guzman C et al: Magnesium deficiency in the Cebus monkey. Circ Res 1963; 12:642-650. 57. Kleiger RE, Seta K, Vitale JJ, et al: Effects of chronic depletion of potassium and magnesium upon the action of acetylstrophanthidin on the heart. Am JCardioll966; 17:520-527. 58. Seller RH, Cangiano J, Kim KE, et al: Digitalis toxicity and hypomagnesemia. Am Heart J 1970; 79:57-68. 59. Boyd LJ, Scherf D: Magnesium sulfate in paroxysmal tachycardia. Am J Med Sci 1943; 206:43-48. 60. Szekely P, Wynne NA: The effects of magnesium on cardiac arrhythmias caused by digitalis. C/in Sci 1951; 10:241-253. 61. Enselburg CD, Simmons HG, Mintz AA: The effects of magnesium upon cardiac arrhythmias. Am Heart J 1950; 39~703-712. 62. Stanbury JB, Farah A: Effects of the magnesium
Acute Digitalis Poisoning
63. 64. 65. 66. 67. 68.
69.
70. 71. 72.
ion on the heart and on its response to digoxin. J Pharmacol Exp Ther 1950; 100:445-453. Volans GN, Holt DW, Ali C: Management of cardiac drug overdose. Resuscitation 1984; 11:207-216. Sharff JA, Bayer MJ: Acute and chronic digitalis toxicity: Presentation and treatment. Ann Emerg Med 1982; 11:327-331. Neff MS, Mendelssohn S, Kim KE, et al: Magnesium sulfate in digitalis toxicity. Am J Cardiol 1972; 291377-382. Seller RH: The role of magnesium in digitalis toxicity. Am Heart J 1971; 82:551-556. Hartel G, Manninen V, Reissel P: Treatment of digoxin intoxication. Lance? 1973: 2:158. Specter MJ, Schweizer E, Goldman RH: Studies on magnesium’s mechanism of action in digitalis-induced arrhythmias. Circulation 1975; 52:1001-1005. Lown B, Cannon RL III, Rossi MA: Electrical stimulation and digitalis drugs: Repetitive response in diastole. Proc Sot Exp Biol Med 1967; 126:698-701. Mason DT, Zelis R, Lee G, et al: Current concepts and treatment of digitalis toxicity. Am J Cardiol 1971; 27~546-559. Lown B: Electrical reversion of cardiac arrhythmias. Br Heart J 1967; 29:469-489. Helfant RH, Sherlag BJ, Damato AN: Protec-
469
tion from digitalis toxicity with the prophylactic use of diphenylhydantoin sodium: An arrhythmic-inotropic dissociation. Circulation 1967; 36:119-125. 73. Rosen M, Lisak, R, Rubin IL: Diphenylhydantoin in cardiac arrhythmias. Am J Cardiol 1967; 20~674-678. 74. Caracta AR, Damato AN, Josephson ME, et al: Electrophysiologic properties of diphenylhydantoin. Circulation 1973; 47:1234-1241. 75. Damato AN, Berkowitz WD, Patton RD, et al: The effect of diphenylhydantoin on atrioventricular conduction in man. Am Heart J 1970; 79:51-56. 76. Procter JD, Baird CL, Wasserman AJ: Adverse effect of bretylium in oubain-induced ventricular tachyarrhythmias (abstract). Circulation 1970; 42(suppl 111):190. 77. Gilles RA, Clancy MM, Anderson RJ: Deleterious effects of bretylium in cats with digitalisinduced ventricular tachycardia. Circulation 1973; 47:974-983. 78. Phillips AF, in Barkin RM, Rosen P (eds): Emergency Pediatrics, St Louis, CV Mosby 1984, p 76. 79. Brady JP, Lewis K: Newborn emergencies, in Pascoe DJ, Grossman M (eds): Quick Reference to Pediatric Emergencies, ed 3. Philadelphia, Lippincott, 1984, p 470.
Medlone,
Vol 4, pp 463-469.
1986
Printed in the USA
l
CopyrIght
ACUTE DIGITALIS POISONING: THE ROLE OF INTRAVENOUS MAGNESIUM Earl J. Reisdorff, Michigan
Reprint
address:
MD,
Michael R. Clark,
digoxin;
poisoning;
Introduction Acute digoxin poisoning is a challenging problem for the emergency medicine specialist. Cardiac glycoside poisoning, from either suicide attempt or accidental ingestion, differs markedly from chronic digitalis toxicity in both clinical presentation and treatment. Early diagnosis and intervention is essential. In digitalis poisoning, magnesium sulfate can be an effective pharmacologic intervention. In 1935
B B RECEIVED:
FACEP,
Journals
Ltd
SULFATE
and Bradford L. Walters,
State University, Affiliated Emergency Medicine Residency, Edward Sparrow Hospital and lngham Medical Center E. Reisdorff, MD, Sparrow Hospital, 1215 E Michigan, Lansing,
Cl Abstract -Acute digitalis poisoning is a complex emergency with a reported mortality rate of 3% to 2Wo.’ In severe overdose, the sodium, potassium-adenosine triphosphatase system is severely inhibited, leading to cardiac dysrhythmias and an elevation of the serum potassium. Magnesium, a cofactor regulating this ion transport system, can successfully treat acute digitalis-induced rhythm disturbances and restore the transmembrane potassium gradient. This paper discusses the cellular mechanism involved in digitalis toxicity and reviews the literature concerning the use of magnesium in acute cardiac glycoside poisoning. 0 Keywordsdigitalis; magnesium; toxicology
MD,
0 1986 Pergamon
MD
MI 48909
Zwillinger reported the use of magnesium sulfate to treat digitalis dysrhythmias.2 Recent case studies and research support magnesium’s efficacy in this life-threatening condition.
Pharmacology
and Mechanism
In adults, gastrointestinal absorption is 60% to 80% of the ingested dose for digoxin and essentially 100% for digitoxin.’ Digoxin is excreted unchanged by the kidneys. Digitoxin is metabolized by the liver, with a significant enterohepatic circulation.“x5 The half-life for digoxin and digitoxin differ, being 1.5 days and 4 to 6 days, respectively.6 For digoxin, the halflife is variable in acute overdose, ‘ml4with some reports describing a biphasic elimination with an initially shortened half-life than a normal or prolonged elimination phase.l1-14 Digitalis exerts a positive inotropic effect on the myocardium. The mechanism proposed by Wilbrandt is that of cardiac glycoside inhibition of the sodium, potassium-adenosine triphosphatase (Na,KATPase) system, which raises the intracellular calcium concentration.” This
Toxicology-one of the most critical and challenging areas confronting the emergency department staff-is coordinated by Kenneth Kulig, MD, of the Rocky Mountain Poison Center.
28 January 1986; ACCEPTED:
19 August 1986 463
0736-4679/86 $3.00 + .OO
464
Table 1. Prominent
E. J. Reisdorff, M. Ft. Clark, and B. L. Walters
Differences
Findings
Between Chronic Digoxin Toxicity and Acute Digoxin Poisoning
Chronic Digoxin Toxicity
Acute Digoxin Poisoning
Noncardiac symptoms
A wide range of gastrointestinal, ocular, CNS, and nonspecific manifestations are commonly present.
Nausea and vomiting are common; other classic symptoms are not reported with consistency.
Cardiac symptoms
Premature ventricular contractions are the most common dysrhythmias; atrial tachycardias, sometimes associated with block, also are seen.
Ventricular dysrhythmias are not common; supraventricular dysrhythmias with heart block are the most characteristic findings; bradycardia is often reported.
Serum potassium on admission
Generally low serum K+ secondary concomitant diuretic therapy.
Normal to elevated serum potassium depending on the degree of Na + , K + ATPase pump inhibition.
Serum digoxin values
Variable but can be within the therapeutic range.
High levels are always seen in patients with symptoms of toxicity.
Serum half-life of digoxin
Reasonably constant in adults and children; close to the same for both groups.
Reported to be shortened in acute poisoning although this has not been consistent.
Reproduced with permission 1976; 35266-77.
of Ekins BR, Watanabe
to
AS: Acute digoxin
increased availability of calcium enhances myocardial contractility. Further studies have shown that the normal efflux of calcium from the myocardial cell is interrupted when the transmembrane sodium gradient is decreased by the Na,K-ATPase inhibition. The subsequent rise in intracellular calcium allows an increase in the number of actin-myosin interactions. In a study by Skou, the myocardial Na,K-ATPase system, which facilitates the efflux of intracellular calcium, was shown to require magnesium as a cofactor.‘6 It is this magnesium-ATPase relationship that forms the pharmacologic basis for using intravenous magnesium in the treatment of digitalis poisoning.
Review of the Literature A review of 35 reports involving 235 cases of massive digitalis ingestions (both suicidal and accidental) revealed 48 deaths, for an overall reported mortality of 20.4V0’-‘~, L7-43.Among children, the mortality was 12.7%, with digoxin being ingested by 8 1% and digitoxin by 8%. There is no statistical relationship between mortal-
poisoning.
Review
of therapy.
Am JHosp
Pharm
ity and the type of digitalis preparation taken. The mortality in adults was 30.39’0, with digoxin taken in 86% of the cases and digitoxin in 6%. When digitalis preparations other than digoxin were ingested, the mortality reached 7 1%. A mortality of 80% was seen in those patients with a digoxin level greater than 25 ng/mL. Of these 35 reports and reviews, only six discuss the use of magnesium in digitalis overdose.7~13~35~36~40 This information emphasizes the potential lethality of digitalis overdose and the need for prompt effective treatment.
Clinical Presentation The effects of acute digitalis overdose differ from those of chronic toxicity (Table l).M The acutely poisoned population tends to be younger and free of ischemic heart disease compared with the older population at risk for chronic toxicity. Hence, they are better able to withstand the toxic insult and are less prone to developing dysrhythmias. Also, in acute digitalis overdose, there are rapid shifts of Na+ and K+ across the myocardial
465
Acute Digitalis Poisoning
Table 2. Common Signs Acute Digitalis Poisoning
and Symptoms
of
CNS: Drowsiness, lethargy, confusion, disorientation, headache, visual disturbances Cardiovascular: Almost any dysrhythmia; most commonly bradycardia and conduction disturbances Gastrointestinal: Nausea, vomiting, abdominal pain, anorexia Electrolytes: Hypokalemia, hyperkalemia
membrane not seen in chronic toxicity, leading to severe electrolyte disturbances. Nausea and vomiting frequently are the first symptoms of digitalis toxicity (Table 2). Diarrhea and abdominal pain may also occur, Mental status changes, such as drowsiness, disorientation, and lethargy are commonly seen. Severe CNS involvement includes agitation and occasionally seizures.23*25B35Photophobia, scotomata, and xanthopsia (yellow vision) are described in chronic toxicity, but are uncommon in acute digitalis poisoning.45-47 Electrolyte disturbances are frequent in massive ingestions. While hypokalemia from diuretic use is associated with chronic toxicity, life-threatening hyperkalemia occurs in acute poisoning.‘4a34*“,4*,49 The acute inhibition of the Na,K-ATPase system can result in a decreased cellular influx of potassium and a consequent rise in serum potassium.6.48 The subsequent change in the membrane potential depresses the myocardial conduction system resulting in conduction delays. These atrioventricular (AV) conduction problems seen in acute digitalis poisoning are exacerbated by a digitalis-induced increase in vagal tone. The rhythm can slow and complete AV dissociation may develop. Ventricular tachycardia and fibrillation, when they occur, are often refractory to resuscitative measures.
Magnesium
and Digitalis
A number of pharmacologic approches to digitalis poisoning have been reported. Magnesium sulfate has stood out as being
efficacious in acute digitalis overdose. Hypomagnesemia is a predisposing and exacerbating factor in digitalis toxicity. Individuals with digitalis toxicity are found to have a higher incidence of hypomagnesemia.s”-54 Vitale found that puppies fed magnesium deficient diets were more sensitive to the toxic effects of digitalis.” As the dogs become hypomagnesemic, they were more prone to develop ventricular tachycardia at lower cardiac glycoside levels. Similar results were found with simians.‘h Another canine study demonstrated that hypomagnesemia prolonged electrocardiographic changes and toxic effects caused by digitalis.57 When hypomagnesemia was achieved by hemodialysis, the amount of cardiac glycoside needed to induce dysrhythmia was significantly lowered.5XIn dogs with digitoxic dysrhythmias, intravenous magnesium sulfate promptly restored a sinus rhythm in 75% of cases. The first reported human use of magnesium to treat digitalis-induced dysrhythmias was by Zwillinger in 1935 .I He used an intracardiac injection of magnesium to control an episode of ventricular tachycardia due to digitalis toxicity. Later, Boyd and Scherf described treating digitalis-induced paroxysmal tachycardias with magnesium. 59 Subsequent reports have continued to show the effectiveness of magnesium in treating digitoxic dysrhythmias.S’-h’
Treatment
of Digitalis
Poisoning
As with any poisoning, identifying the offending agent, removing or neutralizing the toxin, and administering antidotal therapy is axiomatic. Ipecac-induced emesis is recommended in the noncomatose patient, but great caution should be exercised.44,63-66 The vagal stimulation from vomiting may induce or worsen an AV block. If a conduction disturbance is seen, atropine (0.5-l .O mg) should be given intravenously (IV) prior to the administration of ipecac. This can also be done before giving ipecac in the patient with a
466 normal sinus rhythm to prevent the precipitation of bradycardia or a conduction disturbance. Activated charcoal is also recommended because it inhibits the gastrointestinal absorption of digoxin.67 Repeated charcoal dosing may be efficacious with both digoxin and digitoxin. Cathartics containing magnesium salts can be administered, but any additional benefit of the magnesium ion in this setting is speculative. An equally effective cathartic is D-sorbitol. All digitalis ingestions require continuous cardiac monitoring until the patient shows no clinical or ECG signs of toxicity. Initial laboratory studies should include serum potassium, magnesium, calcium, creatinine, and digoxin levels. The serum potassium should be frequently assessed in the early phase of treatment because severe derangements are common and occur rapidly. Serum digoxin levels may have some predictive value. A review of 235 cases of massive digitalis ingestions shows that if the value remains below 2.0 rig/ml, the mortality is 10w.‘-~~J’-~~ Because hyperkalemia may rapidly develop, replacement of potassium should be undertaken with caution in the hypokalemic patient. With Na,K-ATPase inhibition, there is an apparent efflux of potassium from the myocardial cells, allowing potassium to accumulate quickly. Magnesium has a beneficial influence should hyperkalemia occur. Neff showed that the digitalis-induced egress of potassium from the myocardium is halted when magnesium sulfate is administered.@ This may be due to the restorative effect of magnesium on the Na, K-ATPase system,@ but Specter proposes that magnesium sulfate directly influences transmembrane shifts of potassium which would bypass the Na, KATPase system.68 Hyperkalemia can be treated with calcium-binding resins. Calcium should not be used to treat digitalisinduced hyperkalemia because calcium may exacerbate digitalis toxicity. The efficacy of routine electrical pacing is questionable. One report advocates
E. J. Reisdorff, M. R. Clark, and B. L. Walters
prophylactic placement of a venticular pacemaker.36 Since cardiac glycosides lower the threshold for pacemaker-induced extrasystole, placement can potentially produce life-threatening dysrhythmias.6g,70 Such dysrhythmias can be particularly difficult to treat. The added myocardial irritability due to digitalis poisoning can result in refractory ventricular fibrillation upon cardioversion.” For digitalis-induced ventricular dysrhythmias, diphenylhydantoin is the agent of choice. It suppresses the tachydysrhythmias without compromising intraventricular conduction.7,72-74 Atrioventricular conduction may even be restored by phenytoin.75 Lidocaine can also be beneficial in treating dysrhythmias in digitalis poisoning. It can suppress ventricular ectopy without influencing AV conduction. Propranolol, quinidine, and procainamide are of limited value. Bretylium is contraindicated because it may worsen preexisting ventricular tachydysrhythmias or precipitate ventricular fibrillation.76s77 As described above, intravenous magnesium is also an effective agent in treating dysrhythmias from digitalis poisoning. In a report of massive digoxin overdose in which ventricular ectopy was refractory to lidocaine and phenytoin, an infusion of magnesium corrected the rhythm disturbance immediately.22 The adult dose of magnesium in treating digitalis toxicity is 2 g of 10% magnesium sulfate given intravenously over 20 minutes. Magnesium sulfate is prepared as a 50% solution for intramuscular use, so it must be appropriately diluted. The effect of a single bolus injection may be short-lived owing to a rapid renal clearance. This may necessitate a continuous infusion of 1 to 2 g/h. If the serum creatinine level is elevated, one must check the serum magnesium level after the initial bolus prior to starting a continuous infusion. A magnesium level should be checked every two hours, with the dose titrated to maintain a serum level of 4 to 5 mEq/L. Deep-tendon reflexes
Acute Dlgltahs Poisonmg
467
and respiratory depression serve as clinical parameters in assessing the magnesium level. If the reflexes or respiratory pattern become depressed, the magnesium infusion should be halted and the level rechecked. When the serum magnesium concentration is too high, neuromuscular paralysis may ensue. When the victim has normal renal function and the deeptendon reflexes are closely monitored, risks from intravenous magnesium are minimal. The reported use of magnesium in children with digitalis overdose is limited and dosage regimens have not been established. For other disorders, the neonatal magnesium dose is 20 mg/kg intramuscularly (IM) or IV over 20 minutes.78.79 Close monitoring for CNS or respiratory depression is imperative and serum levels should be checked frequently, as in adults.
Digoxin specific Fab antibody fragments show great promise in the treatment of digitalis overdose.30a32s33 Until they are more readily available, magnesium may prove to be an effective temporizing measure.
Summary In conclusion, magnesium is an effective adjunct in the treatment of massive digoxin poisoning. A 3% to 25% mortality rate is associated with this emergency. Intravenous magnesium is a safe, effective pharmacologic intervention, proven to be useful in suppressing digitalis-induced dysrhythmias. Until more definitive therapy is available, magnesium is a useful, potentially life-saving agent in the acute management of digitalis poisoning.
REFERENCES I. Goodman LS: Digitalis in Haddad, LM, Winchester JF (eds): Clinical Management of Poisoning and Drug Overdose, Philadelphia, WB Saunders, 1983, p. 813. 2. Zwillinger L: Uber die Magnesiumwirkung auf das Herz. K/in Wochenschr 1935; 14:1429-1433. 3. Lisalo E: The clinical pharmacokinetics of digoxin. Clin Pharmacokinet 1977; 2:1-16. 4. Doherty JE, DeSoyza N, Kane JJ. et al: Clinical pharmakinetics of digitalis glycosides. Prog Cardiovasc Dis 1978; 21:141-58. 5. Storstein L: Studies on digitalis III: Biliary excretion and enterohepatic circulation of digitoxin and its cardioactive metabolites. Clin Pharmacol Ther 1975; 17:313-20. 6. Smith TW: Digitalis glycosides, N Eng/ J Med 1973; 288:719-722. 7. Rumack RH, Wolfe RR, Gilfrich H: Phenytoin (diphenylhydantoin) treatment of massive digoxin overdose. Br Heart J 1974; 36:405-408. 8. Pearce G, Buchanan N, Uther J: Massive digoxin ingestion in a child. Med / Aust Sept 1980; 279-80. 9. Fresard F, Balant L, Noble J, et al: Cholystryramine et intoxication a la digoxine: Efficacite therapeutique? Schweiz. Med Wochenschr 1979; 109:431-436. IO. Hobson JD, Zettner A: Digoxin serum half-life following suicidal digoxin poisoning. JAMA 1973; 233:147-149. Il. Bertler A, Gustafson A, Redors A: Massive digoxin intoxication: Report of two cases with pharmacokinetic correlations. Acta Med Stand 1973; 194:245-249.
12. Stopfkuchen H, Gilfrich HJ, Jungst BK, et al: Massive digoxin intoxication in childhood. Intensive Care Med 1978; 4: 199-201. 13. Ng RH, Stempsey W, Statland BE: Biphasic profile in the elimination of digoxin from serum after a massive overdose (letter). C/in Chem 1983; 29~393-394. 14. Smith TW, Willerson JT: Suicidal and accidental digoxin ingestion: Report of five cases with serum digoxin level correlations. Circulation 1971; 44:29-36. 15. Wilbrandt W: Zum Wirkingmechanisms des Herzglycosides. Schweiz Med Wochenschr 1955; 85:315-320. 16. Skou JC: The influence of some cations on an adenosine triphosaphate from peripheral nerves. Biochem Biophys Acta 1957; 23:394-401. 17. Holt DW, Trail1 TA, Brown CB: The treatment of digoxin overdose. Clin Nephrol 1975; 3: 119-122. 18. Steentoft A: Fatal digitalis poisoning. Acfa Phar-
macol Toxicol1973; 321353-357. 19. Duke M: Atrioventricular block due to accidental digoxin ingestion treated with atropine. Am
J
Dis Child 1972; 1241745-756. 20. Navab F, Honey M: Self-poisoning with digoxin: Successful treatment with atropine. Br Med J 1967; 3:660-661. 21. Buchanan J: Self-poisoning with digitalis glycosides. BrMed J 1967; 3:661-662. 22. French JH, Thomas RG, Siskind AP et al: Magnesium therapy in massive digoxin intoxication. Ann Emerg Med 1984; 13:562-566. 23. Asplund J, Edhag 0, Mogensen L, et al: Four
468 cases of massive digitalis poisoning. Acta Med &and 1971; 189:293-297. 24. Greenburg M: Accidental digoxin poisoning in a child of 2 years. Arch Dis Child 1957; 32:359-360. 25. Freeman R, Farrar JF, Roberton SEJ: Accidental digitalis poisoning in childhood. Med J Aust Ott 1961:655-659. 26. McNamara DG, Brewer EJ, Ferry GD: Accidental poisoning of children with digitalis. N Engl J Med 1964; 271:1106-l 108. 27. Iisalo E, Nuutila M: Myocardial digoxin concentrations in fatal intoxications. Lancer 1973; 1:257. 28. Nicholls DP: Fatal digoxin overdose. Postgrad Med J 1977; 53:280-281. 29. Maheswaran R, Bramble MG, Hardisty CA: Massive digoxin overdose: Successful treatment with intravenous amiodarone. Br Med J 1983; 287:392-393. 30. Murphy DJ, Bremner WF, Haber E, et al: Massive digoxin poisoning treated with Fab fragments of digoxin-specific antibodies. Pediatrics 1982; 70:472-473. 31. Smiley JW, March NM, Del Guerico ET Hemoperfusion in the management of digoxin toxicity. JAMA 1978; 240~2736-2737. 32. Smith TW, Butler VP, Haber E, et al: Treatment of life-threatening digitalis intoxication with digoxin-specific Fab antibody fragments. N Engl J Med 1982; 307:1357-1357. 33. Rozkovec A, Coltart DJ: Treatment of digoxin overdose with antigen-binding fragments of digoxin-specific antibodies. Br Med J 1982; 285:1315-1316. 34. Reza MJ, Kobick RB, Shine Kl, et al: Massive intravenous digoxin overdosage. N Engl J Med 1974; 291:777-778. 35. Fowler RS, Rathi, L, Keith JD: Accidental digitalis intoxication in children. J Pediatr 1964; 64:188-200. 36. Bismuth C, Motte G. Conso F. et al: Acute diaitoxin intoxication treated by intracardiac pacemaker: Experience in sixty-eight patients. Clin Toxicoll977; 10:433-456. 37. Bergy GC, Fergus EB, Bruce RA: Acute massive digitoxin poisoning: Report of a case and review of the literature. Ann Intern Med 1957; 46:964-976. 38. Bernstein MS, Neschis M, Collini F: Treatment of acute massive digitalis poisoning by administration of a chelating agent. N Engl J Med 1959:261:961-963. 39. Bremner WF, Third JL, Lawrie TDV: Massive digoxin ingestion; Report of a case and review currently available therapies. Br Heart J 1977; 39:688-692. 40. Dyckner T, DeFaire U, Webster PO: Intracellular electrolytes in cardiac and skeletal muscle in fatal digitalis intoxication. Br Heart J 1977; 39:1029-1032. 41. Leeks SR: Suicide by digitalis. NZ Med J 1966; 65:167-168. 42. Citrin D, Stevenson IH, G’Malley K: Massive digoxin overdose: Observations on hyperka-
E. J. Reisdorff, M. R. Clark, and B. L. Walters laemia and plasma digoxin levels. Scott Med J 1972; 17~275-277. 43. Wharton CFP: Attempted suicide by digoxin self administration and its management. G,v Hosp Rep 1970; 119:243-25 1. 44. Ekins BR, Watanabe AS: Acute digoxin poisonings: Review of therapy. Am J Hosp Pharm 1978; 35:268-277. 45. Volpe BT, Soave R: Formed visual hallucinations as digitalis toxicity. Ann Intern Med 1979; 91:865-866. 46. Aronson JK: Digitalis intoxication. Clin Sci 1983; 64:253-258. 47. Lely AH, Van Enter CHJ: Large-scale digitoxin intoxication. Br Med J 1970; 3:737-740. 48. Bismuth C, Gaultier M, Conso F, et al: Hyperkalemia in acute digitalis poisoning: Prognostic significance and therapeutic implications. C/in Toxicoll973; 6:153-162. 49. Goldfrank LR, Kirstein R: Digoxin, in Goldfrank LR (ed): Toxicologic Emergencies: A Comprehensive Handbook in Problem Solving, ed 2. New York, Appleton-Century-Crofts 1982, p. 347-353. 50. Belier GA, Hood WB Jr, Smith TW, et al: Correlation of serum magnesium levels and cardiac digitalis intoxication. Am J Cardiol 1974; 33:225-229. 51. Kim YW, Andrews, CE, Ruth WE: Serum magnesium and cardiac arrhythmias with special reference to digitalis intoxication. Am J Med Sci 1961; 242:87-92. 52. Singh RB, Dube KP, Srivastav PK: Hypomagnesemia in relation to digoxin intoxication in children. Am Heart J 1976; 92:144-147. 53. Cohen L, Kitzes R: Magnesium sulfate and digitalis-toxic arrhythmias. JAMA 1983; 249:2808-2810. 54. Belier GA, Hood WB, Smith TW, et al: Prevalence of hypomagnesemia in a prospective clinical study of digitalis intoxication (abstract). Am J Cardioll970; 26~625. 55. Vitale JJ, Hellerstein EE, Nakamura M, et al: Effects of magnesium-deficient diet upon puppies. Circ Res 1961; 9~387-394. 56. Vitale JJ, Velez H, Guzman C et al: Magnesium deficiency in the Cebus monkey. Circ Res 1963; 12:642-650. 57. Kleiger RE, Seta K, Vitale JJ, et al: Effects of chronic depletion of potassium and magnesium upon the action of acetylstrophanthidin on the heart. Am JCardioll966; 17:520-527. 58. Seller RH, Cangiano J, Kim KE, et al: Digitalis toxicity and hypomagnesemia. Am Heart J 1970; 79:57-68. 59. Boyd LJ, Scherf D: Magnesium sulfate in paroxysmal tachycardia. Am J Med Sci 1943; 206:43-48. 60. Szekely P, Wynne NA: The effects of magnesium on cardiac arrhythmias caused by digitalis. C/in Sci 1951; 10:241-253. 61. Enselburg CD, Simmons HG, Mintz AA: The effects of magnesium upon cardiac arrhythmias. Am Heart J 1950; 39~703-712. 62. Stanbury JB, Farah A: Effects of the magnesium
Acute Digitalis Poisoning
63. 64. 65. 66. 67. 68.
69.
70. 71. 72.
ion on the heart and on its response to digoxin. J Pharmacol Exp Ther 1950; 100:445-453. Volans GN, Holt DW, Ali C: Management of cardiac drug overdose. Resuscitation 1984; 11:207-216. Sharff JA, Bayer MJ: Acute and chronic digitalis toxicity: Presentation and treatment. Ann Emerg Med 1982; 11:327-331. Neff MS, Mendelssohn S, Kim KE, et al: Magnesium sulfate in digitalis toxicity. Am J Cardiol 1972; 291377-382. Seller RH: The role of magnesium in digitalis toxicity. Am Heart J 1971; 82:551-556. Hartel G, Manninen V, Reissel P: Treatment of digoxin intoxication. Lance? 1973: 2:158. Specter MJ, Schweizer E, Goldman RH: Studies on magnesium’s mechanism of action in digitalis-induced arrhythmias. Circulation 1975; 52:1001-1005. Lown B, Cannon RL III, Rossi MA: Electrical stimulation and digitalis drugs: Repetitive response in diastole. Proc Sot Exp Biol Med 1967; 126:698-701. Mason DT, Zelis R, Lee G, et al: Current concepts and treatment of digitalis toxicity. Am J Cardiol 1971; 27~546-559. Lown B: Electrical reversion of cardiac arrhythmias. Br Heart J 1967; 29:469-489. Helfant RH, Sherlag BJ, Damato AN: Protec-
469
tion from digitalis toxicity with the prophylactic use of diphenylhydantoin sodium: An arrhythmic-inotropic dissociation. Circulation 1967; 36:119-125. 73. Rosen M, Lisak, R, Rubin IL: Diphenylhydantoin in cardiac arrhythmias. Am J Cardiol 1967; 20~674-678. 74. Caracta AR, Damato AN, Josephson ME, et al: Electrophysiologic properties of diphenylhydantoin. Circulation 1973; 47:1234-1241. 75. Damato AN, Berkowitz WD, Patton RD, et al: The effect of diphenylhydantoin on atrioventricular conduction in man. Am Heart J 1970; 79:51-56. 76. Procter JD, Baird CL, Wasserman AJ: Adverse effect of bretylium in oubain-induced ventricular tachyarrhythmias (abstract). Circulation 1970; 42(suppl 111):190. 77. Gilles RA, Clancy MM, Anderson RJ: Deleterious effects of bretylium in cats with digitalisinduced ventricular tachycardia. Circulation 1973; 47:974-983. 78. Phillips AF, in Barkin RM, Rosen P (eds): Emergency Pediatrics, St Louis, CV Mosby 1984, p 76. 79. Brady JP, Lewis K: Newborn emergencies, in Pascoe DJ, Grossman M (eds): Quick Reference to Pediatric Emergencies, ed 3. Philadelphia, Lippincott, 1984, p 470.