A Bitter Tale
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《新英格兰医药杂志》
To the Editor: In the Clinical Problem-Solving article by Newman et al. (Aug. 5 issue),1 concerning a case of accidental foxglove poisoning, the discussant fails to comment on the short QT interval evident on the initial electrocardiogram obtained in the emergency department. The QT interval appears to be 360 msec, and the corrected QT interval 280 msec. A short QT interval in the absence of hypercalcemia is specific for digoxin toxicity.2,3 Digitalis glycosides bind specifically to Na+/K+–ATPase, decreasing the active transport of sodium. The increase in intracellular sodium causes an augmentation of the exchange of intracellular sodium for extracellular calcium. This shift can cause an increase in permeability to potassium; an increase in the outward current during the plateau phase, with a reduction in the duration of the action potential; and a short QT interval.4 Recognition of the short QT interval on the initial electrocardiogram could have led to earlier diagnosis of digitalis toxicity and earlier initiation of the appropriate therapy.
Sanjeev B. Goyal, M.D.
David Spodick, M.D., D.Sc.
University of Massachusetts Medical School
Worcester, MA 01655
sangoy@pol.net
References
Newman LS, Feinberg MW, LeWine HE. A bitter tale. N Engl J Med 2004;351:594-599.
Saner HE, Lange HW, Pierach CA, Aeppli DM. Relation between serum digoxin concentration and the electrocardiogram. Clin Cardiol 1988;11:752-756.
Vella A, Gerber TC, Hayes DL, Reeder GS. Digoxin, hypercalcaemia, and cardiac conduction. Postgrad Med J 1999;75:554-556.
Bassingthwaighte JB, Fry CH, McGuigan JA. Relationship between internal calcium and outward current in mammalian ventricular muscle: a mechanism for the control of action potential duration? J Physiol 1976;262:15-37.
To the Editor: As Newman et al. point out, digitoxin is the active agent in the foxglove leaf. Digitoxin has an enterohepatic circulation pattern, which can be effectively interrupted by the administration of colestipol or cholestyramine.1 It has been shown that the elimination of digitoxin can be accelerated considerably by treatment with these resins.2 Such treatment might have shortened the hospital stay in the case Newman et al. describe.
Michael M. Ritter, M.D.
Klinikum Ibbenbueren
D-49477 Ibbenbueren, Germany
m.ritter@klinikum-ibbenbueren.de
References
Caldwell JH, Greenberger NJ. Interruption of the enterohepatic circulation of digitoxin by cholestyramine. I. Protection against lethal digitoxin intoxication. J Clin Invest 1971;50:2626-2637.
Caldwell JH, Bush CA, Greenberger NJ. Interruption of the enterohepatic circulation of digitoxin by cholestyramine. II. Effect on the metabolic disposition of tritium-labeled digitoxin and cardiac systolic intervals in man. J Clin Invest 1971;50:2638-2644.
The authors reply: Goyal and Spodick comment on the important association of a shortened QT interval with digitalis toxicity. We would like to point out, however, that a shortened QT interval may occur for many reasons other than hypercalcemia or digoxin toxicity (e.g., hyperkalemia, hyperthermia, and changes in autonomic tone, as in a familial syndrome1) or may occur with normal digoxin levels and no symptoms of toxicity.2 However, we agree that in combination with the findings on the electrocardiogram (sinus bradycardia and ST-segment depressions with a "scooping" appearance), the shortened QT interval certainly adds to the suspicion of a digitalis effect that was raised in the case discussion, and we agree that this finding may have led to an earlier diagnosis.
Ritter points out the binding action of cholestyramine to digitoxin within the intestine. Digitoxin is primarily excreted by the kidney, but some digitoxin is excreted in the bile and reabsorbed by the enterohepatic circulation. Cholestyramine will bind to digitoxin when both are ingested simultaneously. Caldwell et al.3,4 suggested that interference with the enterohepatic cycling of digitoxin could lower its serum levels and decrease its cardiac effects. However, we could not find studies to confirm that the outcome of digitalis intoxication is improved with cholestyramine.
Lori S. Newman, M.D., Ph.D.
Mark W. Feinberg, M.D.
Howard E. LeWine, M.D.
Brigham and Women's Hospital
Boston, MA 02115
lnewman1@partners.org
References
Gaita F, Giustetto C, Bianchi F, et al. Short QT syndrome: a familial cause of sudden death. Circulation 2003;108:965-970.
Hornestam B, Held P, Edvardsson N. Effects of digoxin on electrocardiogram in patients with acute atrial fibrillation -- a randomized, placebo-controlled study. Clin Cardiol 1999;22:96-102.
Caldwell JH, Greenberger NJ. Interruption of the enterohepatic circulation of digitoxin by cholestyramine. I. Protection against lethal digitoxin intoxication. J Clin Invest 1971;50:2626-2637.
Caldwell JH, Bush CA, Greenberger NJ. Interruption of the enterohepatic circulation of digitoxin by cholestyramine. II. Effect on the metabolic disposition of tritium-labeled digitoxin and cardiac systolic intervals in man. J Clin Invest 1971;50:2638-2644.
Sanjeev B. Goyal, M.D.
David Spodick, M.D., D.Sc.
University of Massachusetts Medical School
Worcester, MA 01655
sangoy@pol.net
References
Newman LS, Feinberg MW, LeWine HE. A bitter tale. N Engl J Med 2004;351:594-599.
Saner HE, Lange HW, Pierach CA, Aeppli DM. Relation between serum digoxin concentration and the electrocardiogram. Clin Cardiol 1988;11:752-756.
Vella A, Gerber TC, Hayes DL, Reeder GS. Digoxin, hypercalcaemia, and cardiac conduction. Postgrad Med J 1999;75:554-556.
Bassingthwaighte JB, Fry CH, McGuigan JA. Relationship between internal calcium and outward current in mammalian ventricular muscle: a mechanism for the control of action potential duration? J Physiol 1976;262:15-37.
To the Editor: As Newman et al. point out, digitoxin is the active agent in the foxglove leaf. Digitoxin has an enterohepatic circulation pattern, which can be effectively interrupted by the administration of colestipol or cholestyramine.1 It has been shown that the elimination of digitoxin can be accelerated considerably by treatment with these resins.2 Such treatment might have shortened the hospital stay in the case Newman et al. describe.
Michael M. Ritter, M.D.
Klinikum Ibbenbueren
D-49477 Ibbenbueren, Germany
m.ritter@klinikum-ibbenbueren.de
References
Caldwell JH, Greenberger NJ. Interruption of the enterohepatic circulation of digitoxin by cholestyramine. I. Protection against lethal digitoxin intoxication. J Clin Invest 1971;50:2626-2637.
Caldwell JH, Bush CA, Greenberger NJ. Interruption of the enterohepatic circulation of digitoxin by cholestyramine. II. Effect on the metabolic disposition of tritium-labeled digitoxin and cardiac systolic intervals in man. J Clin Invest 1971;50:2638-2644.
The authors reply: Goyal and Spodick comment on the important association of a shortened QT interval with digitalis toxicity. We would like to point out, however, that a shortened QT interval may occur for many reasons other than hypercalcemia or digoxin toxicity (e.g., hyperkalemia, hyperthermia, and changes in autonomic tone, as in a familial syndrome1) or may occur with normal digoxin levels and no symptoms of toxicity.2 However, we agree that in combination with the findings on the electrocardiogram (sinus bradycardia and ST-segment depressions with a "scooping" appearance), the shortened QT interval certainly adds to the suspicion of a digitalis effect that was raised in the case discussion, and we agree that this finding may have led to an earlier diagnosis.
Ritter points out the binding action of cholestyramine to digitoxin within the intestine. Digitoxin is primarily excreted by the kidney, but some digitoxin is excreted in the bile and reabsorbed by the enterohepatic circulation. Cholestyramine will bind to digitoxin when both are ingested simultaneously. Caldwell et al.3,4 suggested that interference with the enterohepatic cycling of digitoxin could lower its serum levels and decrease its cardiac effects. However, we could not find studies to confirm that the outcome of digitalis intoxication is improved with cholestyramine.
Lori S. Newman, M.D., Ph.D.
Mark W. Feinberg, M.D.
Howard E. LeWine, M.D.
Brigham and Women's Hospital
Boston, MA 02115
lnewman1@partners.org
References
Gaita F, Giustetto C, Bianchi F, et al. Short QT syndrome: a familial cause of sudden death. Circulation 2003;108:965-970.
Hornestam B, Held P, Edvardsson N. Effects of digoxin on electrocardiogram in patients with acute atrial fibrillation -- a randomized, placebo-controlled study. Clin Cardiol 1999;22:96-102.
Caldwell JH, Greenberger NJ. Interruption of the enterohepatic circulation of digitoxin by cholestyramine. I. Protection against lethal digitoxin intoxication. J Clin Invest 1971;50:2626-2637.
Caldwell JH, Bush CA, Greenberger NJ. Interruption of the enterohepatic circulation of digitoxin by cholestyramine. II. Effect on the metabolic disposition of tritium-labeled digitoxin and cardiac systolic intervals in man. J Clin Invest 1971;50:2638-2644.