Withering Heights: A Tale of Digitalis

Digitalis, a cardiac glycoside, is an age-old drug used since the time of the Romans. It wasn’t until the 18th century when the study of digitalis propelled humankind into the age of modern medicinal therapeutics. The cardiac glycosides are isolated from the foxglove and were espoused by William Withering, a famous physician and herbalist of his time in England. At that time, digitalis became the cornerstone treatment for congestive heart failure (CHF) and atrial fibrillation. At that time, CHF was known as dropsy referring to patients with edematous states, although no one had differentiated cardiac dropsy from similar edematous states of liver and renal disease. [1]

William Withering
Birmingham Portraits collection

Foxglove Plant

A foxglove farm in Minnesota, ca. 1900.
NATIONAL LIBRARY OF MEDICINE

Early, classic descriptions of digitalis can be found in records by Dioscorides and Galen. Leonard Fuchs described the plant in his 1542 publication, Historia stirpem, in which he recommended it for the treatment of dropsy. However, Withering was the first to scientifically analyze Digitalis and study its dosage and toxicity. In 1785, he published An Account of the Foxglove and Some of Its Medical Uses; With Practical Remarks on Dropsy and Other Diseases, where he described his ‘experiments’ with using the drug on patients. He discovered that the dried powdered leaf was more effective than the fresh leaf. The powder was also better than a decoction, as boiling seemed to destroy some of the active principle. Undertaking studies of more than 100 patients, Withering connected the relation between diuresis and improvement of CHF symptoms. He observed that digitalis may improve the ‘tumultuous action of the heart.’ He was also the first to describe the toxicities of digitalis which included nausea, vomiting, diarrhea, and green/yellow vision, and he was the first to state digitalis should be stopped and restarted at a lower dose when such symptoms occurred. Withering was the first to note that some forms of dropsy did not respond to digitalis; these cases were likely ascites from cirrhosis and renal failure. [2] It is postulated by some historians that digitalis helped create the unique style and color palette of a yellow-obsessed Vincent van Gogh who had been using it erroneously for the treatment of epilepsy. In 1875, famed German chemist Oswald Schmiedeberg isolated the first pure glycoside in crystal form from foxglove triggering the pharmacologic development of digitalis as a widespread cardiac drug and the rest of the pharmaceutical industry. The use of digitalis has since decreased in the last few decades. Its narrow therapeutic index combined with advances in cardiology and pharmacology have left it out of the spotlight in favor new agents such as diuretics, ACE inhibitors, ARBs, beta-blockers, and aldosterone antagonists. [3]

Digitalis Physiology

Digitalis is a cardiac glycoside with positive inotropic activity as well anti-arrhythmic activity; it also has AV nodal blocking activity, useful for atrial fibrillation. Digitalis works by increases refractory period and decreases conduction velocity, causing positive inotropic effect, decreased ventricular rate, and enhanced vagal tone.

Digitalis is hence often prescribed for patients in atrial fibrillation, especially if they have been diagnosed with CHF. The American College of Cardiology/American Heart Association guidelines recommend digoxin for patients with symptomatic chronic heart failure and reduced systolic function, preservation of systolic function, and/or rate control for atrial fibrillation with a rapid ventricular response. The Digitalis Investigation Group NEJM trial however did not find any change in mortality with use of digoxin in CHF but did find decreased hospitalizations and slowing of chronic CHF progression. The AFFIRM trial showed no superiority of rate versus rhythm control in atrial fibrillation with rapid ventricular response but noted less side effects of rate controlling agents such as beta blockers, calcium channel blockers, and digitalis. [4] [5] 

Digoxin in the Emergency Department

Although digoxin toxicity has become less common, it is important for the EM physician to keep an eye out for it as it can be fatal. Digoxin toxicity can be acute or chronic. According to the AAPCC (American Association of Poison Control Centers), there were 1,336 single exposures to plant cardiac glycosides and 1,601 single exposures to drug cardiac glycosides in 2011. These are much fewer when compared to calcium channel blocker toxicity (5,140 cases) and beta-blocker cases (10,485 cases). Despite the fewer reported cases, there were 27 deaths attributed to digitalis compared to 26 and 9 from calcium channel blockers and beta-blockers, respectively. [6]

Some causes and triggers for which EM physicians should look include advanced age, acute coronary syndrome, hypothyroidism, hypercalcemia renal insufficiency, hyperthyroidism, hypoxemia, acid-base imbalance, and a host of medications including cardiac drugs such as amiodorone, beta blockers, and calcium channel blockers.

In acute toxicity, GI symptoms such as nausea and vomiting may be prominent. Cardiac signs such as dysrhythmias and hemodynamic collapse can occur. Chronic toxicity can result nonspecific symptoms such as malaise, weakness, weight loss, and rarely the classic visual disturbances (halos around lights). Digoxin toxicity also can cause CNS symptoms ranging from headache to frank altered mental status. In conjunction with the clinical picture, the workup for suspected digoxin toxicity relies on the obtaining the following studies: ECG, serum digoxin level, electrolytes, and renal function studies. Serum digoxin measurement can lead to both false negative and false positive results and difficulty in interpretation between acute and chronic toxicity. Trending digoxin levels may be more useful in the resuscitation of a digoxin poisoned patient. [7]

Digoxin and the Electrocardiogram

ECG findings can be variable. The classic findings are increased automaticity with decrease AV conduction – paroxysmal atrial tachycardia with slow ventricular rate. The more common findings include ventricular ectopy such as unifocal or multifocal PVCs with bigeminy or trigeminy, and various degrees of heart block. Other ECG findings include junctional (AV nodal) tachycardia, and ventricular tachycardia. Bidirectional ventricular tachycardia is a virtually pathognomonic finding for digoxin toxicity. [8]

Though not necessarily a finding in toxicity, a patient on digitalis may show the  ‘digitalis effect,’ seen as ‘scooped’ or ‘Salvador Dali mustache’ ST depression. Nonspecific T wave changes may be seen, along with U waves, QT shortening and PR prolongation.

Coarse atrial fibrillation with high degree AV block, junctional escape rhythm (regularized Afib)

Bidirectional VT

PAT with AV block

Ventricular Bigeminy

Digitoxin Effect (Salvador Dali-like QRS-ST segment)

 EKG images taken from http://lifeinthefastlane.com/ecg-library/basics/digoxin-toxicity Credit: Ed Burn

Treatment

Treatment of digitalis toxicity depends on clinical presentation, ECG findings, and degree of hemodynamic stability. Electrolyte management is critical, especially with regards to hyperkalemia, which is common in acute toxicity. Hypokalemia and hypomagnesemia are usually seen in chronic toxicity. Hyperkalemia should not be treated with calcium in these cases due to the theoretical risk of worsening ventricular ectopy. Hypercalcemia should be treated as it can precipitate digoxin toxicity. Digoxin-specific Fab fragments is a revolutionary antidote in the treatment of digoxin toxicity, and it should be considered in any presentation of severe, life-threatening cardiac toxicity, known massive ingestion, end organ dysfunction, rapid deterioration, hemodynamic compromise, or hyperkalemia with K+ greater than 5. Adverse effects include worsening CHF, tachydysrhythmias, and hypokalemia from reversal of therapeutic digoxin levels. In case of acute toxicity, activated charcoal should be considered. Binding resins may be considered, especially in patients with poor renal function. Supportive care should be administered, including IV fluids, monitoring, and oxygenation. Management of bradydysrhythmias and supraventricular tachydysrhythmias is with supportive therapies; atropine may be useful for symptomatic bradydysrhythmias especially in acute ingestion. Ventricular tachycardia may be treated with phenytoin or lidocaine as amiodorone, quinidine, and procainamide are contraindicated. Magnesium should be considered in patients in ventricular fibrillation or ventricular tachycardia if Fab cannot be obtained immediately. Magnesium should not be used in cases of bradycardia or AV block and should be used cautiously in renal failure patients. Cardioversion for severe dysrhythmias is dangerous as it may precipitate ventricular fibrillation and asystole in digitalis toxicity; however, if the patient is hemodynamically unstable with a wide complex tachycardia it should be performed. Some have suggested starting cardioversion at 50-100J rather than 100J as seen in ACLS protocol. [9,10,11]

Disposition

Any patient with evidence of digoxin toxicity should be admitted. ICU admission is encouraged for any patient with hemodynamic instability, need for Fab administration, or hyperkalemia.

Works Cited

  1. Aronson JK (1985). An account of the foxglove and its medical uses 1785-1985. Oxford: Oxford University Press.
  2. Lee MR (2001). William Withering (1741-1799): A Birmingham Lunatic. Proceedings of the Royal College of Physicians of Edinburgh 31:77-83.
  3. Tröhler U (2003). Withering’s 1785 appeal for caution when reporting on a new medicine. In: The James Lind Library (jameslindlibrary.org).
  4. Weisse, Allen B. “A fond farewell to the foxglove? The decline in the use of digitalis.” Journal of cardiac failure1 (2010): 45-48. Withering W (1785). An account of the foxglove and some of its medical uses: with practical remarks on dropsy and other diseases. London: J and J Robinson
  5. Wyse, D. G., et al. “A comparison of rate control and rhythm control in patients with atrial fibrillation.” N Engl J Med23 (2002): 1825-33.
  6. Bronstein AC, Spyker DA, Cantilena LR Jr, Rumack BH, Dart RC. 2011 Annual report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 29th Annual Report. Clin Toxicol (Phila). 2012 Dec. 50(10):911-1164.
  7. See I, Shehab N, Kegler SR, Laskar SR, Budnitz DS. Emergency department visits and hospitalizations for digoxin toxicity: United States, 2005 to 2010.Circ Heart Fail. 2014 Jan. 7 (1):28-34. [Medline]. [Full Text].
  8. Mahdyoon H, Battilana G, Rosman H, Goldstein S, Gheorghiade M. The evolving pattern of digoxin intoxication: observations at a large urban hospital from 1980 to 1988.Am Heart J. 1990 Nov. 120(5):1189-94.[Medline].
  9. Yang EH, Shah S, Criley JM. Digitalis toxicity: a fading but crucial complication to recognize. Am J Med. 2012 Apr. 125(4):337-43.
  10. http://lifeinthefastlane.com/ecg-library/basics/digoxin-toxicity/
  11. Trial, Main, and Digitalis Investigation Group. “The effect of digoxin on mortality and morbidity in patients with heart failure.” N Engl J Med336 (1997): 525-33.
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