Digitalis Intoxication Following Conversion to Sinus Rhythm

Transcription

1 Digitalis Intoxication Following Conversion to inus Rhythm Downloaded from by on November 11, 218 By ROBERT GILBERT, M.D., AND RICHARD P. IN 1963 a study was published from our laboratory concerning cardiac performance during exercise before and after conversion from atrial fibrillation to sinus rhythm.' All subjects were receiving digitalis at the time of conversion. One of the findings of that study was a markedly low heart rate at exercise in sinus rhythm, much lower than expected for a group of subjects with a comparable degree of cardiac disability. Furthermore, electrocardiographic abnormalities suggesting digitalis intoxication often occurred after conversion, even in subjects who showed no evidence of digitalis intoxication prior to conversion. These results led to the speculation that digitalis requirements might be less in sinus rhythm than in atrial fibrillation. The conversions in the above-mentioned study were accomplished with quinidine, usually in a dose range of 1 to 3 Gm. over a period of 8 hours. The role of these relatively large doses of quinidine in either potentiating or suppressing this phenomenon of digitalis intoxication could not be assessed. The recent introduction of direct-current countershock for the treatment of cardiac arrhythmias2 has made it possible to circumvent this difficulty. The present report is a study of the results of conversion to sinus rhythm with direct-current countershock with special emphasis on the appearance of digitalis intoxication. The subjects received either no quinidine or much smaller doses than those previously used for conversion. From the Department of Medicine, tate University of New York, Upstate Medical Center, and the Veterans Administration Hospital, yracuse, New York. Dr. Gilbert is the recipient of a United tates Public Health ervice Research Career Development Award. CUDDY, M.D. Methods The records of 44 patients receiving directcurrent countershock for the treatment of cardiac arrhythmias were reviewed. The patients were divided into four groups. Group 1 (table 1) consisted of 28 patients successfully converted from atrial fibrillation or flutter to sinus rhythm who were receiving a digitalis preparation up to or within 2 days of the time of conversion. Group 2 (table 2) consisted of five patients successfully converted from ventricular tachycardia or ventricular fibrillation to sinus rhythm who were not receiving digitalis. Group 3 consisted of six patients receiving digitalis who were given countershock for conversion of atrial fibrillation or flutter but who did not convert. Group 4 (table 4) consisted of five patients converted from atrial fibrillation or flutter who either were not receiving digitalis or who were taken off digitalis for at least 5 days prior to conversion. In the immediate period after countershock many patients demonstrated ventricular or nodal arrhythmias that usually disappeared within 1 minute. The electrocardiograms reported after conversion are not from this immediate period after countershock, but rather are tracings taken from hours to 3 days following countershock. A patient was considered to show the occurrence of bradycardia when the heart rate was above 6 in atrial fibrillation and below 6 in sinus rhythm. An increase in ventricular extrasystoles was considered to have occurred following conversion when frequent (at least one in six normal complexes) or multifocal ventricular extrasystoles appeared in sinus rhythm when the electrocardiogram prior to conversion showed no or only an occasional extrasystole. A change from no ventricular extrasystoles to an occasional one was not considered significant, since occasional extrasystoles might be missed in a routine electrocardiogram. Results The details of the electrocardiograms before and after conversion in subjects receiving digitalis at the time of conversion (group 1) are shown in table 1. Those features of the post-conversion electrocardiograms suggesting

2 Downloaded from by on November 11, 218 DIGITALI INTOXICATION TER COUNTERHOCK digitalis intoxication are summarized in table 3. Of 28 successful conversions, electrocardiographic abnormalities compatible with digitalis intoxication were found in 2 cases, representing 72 per cent of the total conversions. There were no changes in T segments following conversion, nor did the patients develop any of the constitutional signs of digitalis intoxication. The five cases receiving countershock for conversion of ventricular tachycardia or fibrillation who were not receiving digitalis (table 2) showed only one instance of firstdegree heart block and none of the other abnormalities noted in the group 1 patients. ix patients in atrial fibrillation or flutter receiving digitalis treated with countershock did not convert (group 3). Four of these demonstrated transient electrocardiographic abnormalities after countershock that persisted at most only a few minutes. There were no instances of bradycardia or prolonged increase in ventricular extrasystoles. Two patients in group 1 died several hours after apparently successful conversion. The first patient, E.B., had a ventricular rate of 6 with multifocal ventricular extrasystoles prior to conversion. Following conversion the rate in sinus rhythm was 55 with first-degree heart block and persistence of the multifocal ventricular extrasystoles. Three hours after conversion, he suddenly developed ventricular fibrillation. This was recognized almost immediately, and resuscitation was started. Further countershock produced transient alterations of rhythm but ventricular fibrillation invariably recurred. In this patient the slow rate in atrial fibrillation and the multifocal ventricular extrasystoles are certainly highly suggestive of digitalis intoxication, even prior to conversion. Two other patients showed multifocal ventricular extrasystoles prior to conversion; both had first-degree heart block in sinus rhythm and persistence of extrasystoles. The second patient who died, V.H., had nothing to suggest digitalis intoxication prior to conversion. Digoxin had been stopped 2 days before conversion. After conversion, she demonstrated ventricular bigeminy for several hours and then suddenly developed ventricular fibrillation several hours following a single oral dose of.25 mg. of digoxin. Again, only temporary reversion of the ventricular fibrillation could be obtained with further countershock. When it was suspected that digitalis intoxication might be responsible for the postconversion arrhythmias, it was decided in subsequent patients to discontinue digitalis for a 5- to 1-day period prior to conversion. Five patients have been converted to date who either never had digitalis or who had prolonged withdrawal (group 4). The results of these conversions are shown in table 4. There were no instances of any of the abnormalities noted in the group-i patients. It was also noted that even the transient ventricular and nodal arrhythmias seen in groups 1 and 3 and thought to be an inevitable manifestation of the countershock were not seen in these patients who had prolonged withdrawal of digitalis prior to conversion. Discussion Two questions are critical. Are the abnormalities noted in sinus rhythm a result of digitalis intoxication? If so, what is the relationship of the digitalis intoxication to the change in rhythm? Concerning the first question, there are of course no pathognomonic electrocardiographic features of digitalis intoxication so the diagnosis must always be presumptive. The fact that the abnormalities were very characteristic of those known to be produced by digitalis is important but of itself not very strong evidence. Digitalis can produce such a wide variety of disturbances that the statement could apply to almost any abnormality noted. everal factors point to digitalis intoxication, however. First, the unusually low heart rates at exercise seen in those subjects converted in the quinidine study are characteristic of the toxic effect of digitalis on the sinoatrial node3 and cannot be easily explained by any other mechanism. The expected effect of the quinidine would be to speed rather than to slow the heart.4 econd, when digitalis was withdrawn and the subjects remained in sinus rhythm, the abnor- 59

3 6 GILBERT, CUDDY Digitalized Patients Converted from Atrial Fibrillation Table or utter to inus Rhythm 1 Downloaded from by on November 11, 218 Case R.D. C.A. L.T. J.I. A.L. H.K. E.B. J.T. M.R. M.R. CL. WE. G.D. A.D. E.M. A.V. M.Ro. B.B. J.C. D.M. W.. A.T. G.P. M.C. T.O. I.C. V.H. P.Q. Diagnosis PMD AHD AHD AHD AHD AHD AHD PMD AHD AHD AHD I Daily.15 DL.875 DX.1 DL.1 DT.1 DT.5 DX.15 DL.1 DT.25 DX.1 DL.1 DT.5 GT.15 DT.25 DX.5 DX.25 DX.1 DT.25 DX.25 DX.5 DT.1 DT.15 DT.3 DT.1 DL.25 DX.1 DT Digitalis Extra or digitalizing.7 DT ex..6 DL,.5 DX 2.5 DX.4 CD ex. 1.2 DT 1.75 DX 1.4 DT 1.6 CD, 1.6 DT 1.6 CD, 2. DT 1.6 DT Quinidine.4.2 QID.2 QID.2 QID.2 QID AHD = arteriosclerotic heart disease, = rheumatic heart disease, PMD primary myocardial disease. For digitalis: DL = digitalis leaf, DT= digitoxin, DX = digoxin, GT = gitaligin, CD = cedilanid. Dosages for digitalis leaf are in grams, all other in milligrams. For Quinidine: TID = 3 times/day, QID = 4 times/day, Pr = procaine amide, Q 4 Hr. = every 4 hours. Dosages are in grams. Where numbers only are shown they are single doses on the day of countershock. = sinus, N nodal, = atrial fibrillation, = atrial flutter, PAT = paroxysmal atrial tachyeardia, V ventricular extrasystoles, = multifocal ventricular beats, VB = ventricular bigeminy, occ. = occasional, freq. = frequent I = idiopathic atrial fibrillation. OHD = organic heart disease, etiology unknown. N.R. = not recorded..2 QID Pr prev. day.2 QID.4 QID.2 QID.2 TID TID QID Q 4 Hr. QID QID.4 QID.2 QID.2 Q 4 Hr..4 Q 4 Hr..2 QID.2,.2,.2.2 Q 4 Hr. Countershock watt seconds 1,2,3 2 1,2 2,3 1 2,34 2 2, ,3 1 2, N.R. 2,3 25 1,2, N.R

4 DIGITALI INTOXICATION TER COUNTERHOCK 61 Downloaded from by on November 11, 218 Pre-shock ECG Rhythm Vent. rate V Post-shock ECG Rhythm Rate Pr s 1.17 PAT N malities disappeared. ubject R.D., for example, developed ventricular bigeminy following conversion. This persisted for 1 month until the question of digitalis intoxication was raised. When digitalis was discontinued, the ventricular bigeminy disappeared. Finally, the abnormalities were in general not noted in those subjects not receiving digitalis or in whom digitalis had been discontinued for V VB Freq VB Comment VB persisted 1 month; stopped after DL stopped DX continued; recurred DL stopped; recurred DT continued; recurred DT continued; reverted to Failed to convert with DC; spontaneous con. next day for 3 hr.; then vent. fib. Patient died DL stopped; 1 days later no extrasystoles DT continued; recurred pontaneous conversion Later ECG showed occ. V Alternating and N; DT continued; 1 days later, still nodal 2:1 block; DT stopped recurred DX reduced; 1 week later, Pr.2 Following conv.; 3:1 block with Wenchebach DT and CD stopped; 1 week later sinus rhythm DT stopped; several weeks later Pr.17 DL stopped; recurred VB persisted several hours; then vent. fib. Patient died several days prior to conversion. Gold5 has studied the interaction of digitalis and quinidine. The combined effect of the two drugs in producing the toxicity noted here cannot be entirely ruled out in some patients. Analysis of several cases, however, suggests that quinidine played a minor role at most. Bradycardia, first- and second-degree heart block, and increased ventricular

5 62 GILBERT) CUDDY Table 2 Patients Converted from Ventricular Tachycardia or Ventricular Fibrillation Not Receiving Digitalis Downloaded from by on November 11, 218 Countershock, Post-conversion ECG Case Diagnosis Quinidine watt seconds Rhythm Rate Pr v Comment E.W..4 QID Next day Pr.22 H.W. AHD 8 shocks level N.R. F.M. AHD.2 QID H.. AHD.2 QID P.M. AHD.2 QID N.R Freq. Abbreviations as in table 1. extrasystoles were seen in subjects receiving no quinidine (L.T., J.T., M.R., W..). ubject R.D., in whom ventricular bigeminy persisted for 1 month, received only a single dose of.4 Gm. of quinidine. ubject W.E. had 1.2 Gm. of quinidine the day prior to conversion and none afterwards, yet nodal rhythm was still present 1 days later. Finally, subjects who developed electrocardiographic abnormalities following conversion showed no significant widening of the QR complex, an indication that quinidine effect was not prominent. That the findings are the result of the change in rhythm from atrial fibrillation or flutter to sinus rhythm is borne out by their absence in those subjects on digitalis receiving countershock but not converting. Also, since similar findings occurred in subjects converted with quinidine, it would appear to be the result of the conversion itself rather than the method used for the conversion. At least two factors can account for the Table 3 Electrocardiographic Abnormalities in 28 Converted ubjects Receiving Digitalis up to Time of Conversiaon Abnormality No. cases First-degree heart block 13 econd-degree heart block 1 Paroxysmal atrial tachycardia with block 1 Appearance of bradycardia 7 Nodal rhythm 2 Increase in ventricular extrasystoles 3 Death in ventricular fibrillation 2 emergence of digitalis intoxication following conversion. Many patients in atrial fibrillation or flutter require large amounts of digitalis for control of the ventricular rate. Obviously, certain manifestations of digitalis intoxication such as first- or second-degree heart block cannot be recognized in atrial fibrillation or flutter. If the digitalis level that produces these toxic effects is lower than that producing ventricular extrasystoles, for example, then this level could be present in atrial fibrillation or flutter with the physician becoming aware of it only after conversion. Another factor may be the slower ventricular rates often seen after conversion.1 6,7 uch a slowing might be just enough to allow an idioventricular focus with a slow rate to become manifest. In certain subjects of this study, however, ventricular extrasystoles appeared in the absence of a slowing of the ventricular rate. The therapeutic implications of the study are clear. It is hazardous to convert a patient from atrial fibrillation or flutter to sinus rhythm when any manifestations suggesting digitalis intoxication are already present. This would hold true regardless of the method used for conversion. It would undoubtedly be wise to withhold digitalis for at least several days in all subjects in whom a conversion attempt is planned. Digitalis intoxication after conversion may actually be the cause of certain cases of sudden death occurring in patients receiving quinidine for the conversion and heretofore attributed to the quinidine.8 Two of the desirable features of directcurrent countershock for conversion of atrial

6 DIGITALI INTOXICATION TER COUNTERHOCK 63 Downloaded from by on November 11, Q IZI) ~ Cd ct c.: N 4 > o 1 Cl1 O 11- -i bc C-e Ili ) Iu c.c i -4 - Ciclton ou e-x I,Juy16 ; i,d A 1 d.. O Cl od Cl1 6 E-4 _s - CZ co CZ ~ *_1. fibrillation are said to be its simplicity9 and that it may require only a day or two of hospitalization.1 Although the present authors believe it to be the method of choice for conversion, our experience has indicated that it is not to be undertaken lightly. One or 2 days off a digitalis preparation is not adequate to insure the absence of digitalis intoxication (V.H., for example). It is our current practice to discontinue short-acting digitalis preparations for at least 5 days and long-acting ones for 1 days prior to conversion. uch withdrawal poses certain problems. One is the risk of a rapid ventricular rate and the appearance of heart failure as the digitalis effect wears off. This has happened once in our experience; rapid redigitalization was instituted and the conversion attempt was abandoned. For this reason we have thus far hospitalized for the entire withdrawal period those patients on shortacting preparations and for the latter half of the period those on long-acting ones. Another risk is that of a conversion to atrial flutter with a 2: 1 or even a 1: 1 ventricular response, which was a recognized danger when converting undigitalized patients with quinidine.1" A 2: 1 response of this nature has also occurred once in our present series in a patient who had been taken off digitalis leaf for 1 days prior to the conversion attempt. It is hoped, as more experience is gained, it will be found that the same favorable results noted in the group-4 patients can be achieved with a shorter withdrawal period, which will both reduce the hazards referred to and shorten the hospital stay. ummary The records of 28 patients receiving digitalis and converted from atrial fibrillation or flutter to sinus rhythm with direct-current countershock were reviewed. Electrocardiographic signs suggesting digitalis intoxication following conversion occurred in 2 of these cases. Two of these patients died as a result of ventricular fibrillation several hours after apparently successful conversion. ix patients on digitalis treated with countershock but not converting and five patients converted with

7 64A countershock who were not receiving digitalis or in whom digitalis had been discontinued for several days failed to show these electrocardiographic abnormalities. The results indicate that digitalis intoxication will often appear following conversion to sinus rhythm when no indication of digitalis intoxication was present prior to conversion. It is recommended that digitalis be withheld for several days in subjects for whom a conversion attempt is planned. GILBERT, CUDDY References 1. GILBERT, R., EIcG, R. H., MULYAN, H., KFIGH- LEY, J., AND AucmNCLO, J. H., JR.: Effect on circulation of conversion of atrial fibrillation to sinus rhythm. Circulation 27: 179, LowN, B., PERLROTH, M. G., KAIDBEY,., ABE, T., AND HARKEN, D. W.: "Cardioversion" of atrial fibrillation. New England J. Med. 269: 325, GOODMAN, L.., AND GILMAN, A.: The Pharmacological Basis of Therapeutics. Ed. 2. New York, The Macmillan Co., 1955, p GOODMAN, L.., AND GILMAN, A.: The Pharmacological Basis of Therapeutics. Ed. 2. New York, The Macmillan Co., 1955, p GOLD, H.: Quinidine in Disorders of the Heart. New York, Paul B. Hoeber, Inc., 195, Chapter BLUMGART, H. L.: The reaction to exercise of the heart affected by auricular fibrillation. Heart 11: 49, WETHERBEE, D. C., BROWN, M. G., AND HOLZ- MAN, D.: Ventricular rate response following exercise during auricular fibrillation and after conversion to normal sinus rhythm. Am. J. M. c. 223: 667, THOMON, G. W.: Quinidine as a cause of sudden death. Circulation 14: 757, LOWN, B.: "Cardioversion" of arrhythmias (II). Mod. Concepts Cardiovas. Dis. 33: 869, BELLET,.: Atrial Fibrillation. J.A.M.A. 189: 419, WOOD, P.: Diseases of the Heart and Circulation. Ed. 2. Philadelphia, J. B. Lippincott Co., 1956, p Downloaded from by on November 11, 218 The Quest for Meanings It is my conviction that no limit should be set on the intellectual content of scientific research. In our quest for meanings we should look for a unifying tradition, for a continuity of ideas evolved by great men, for their grasp of and their addition to what their predecessors knew, and also for the large schemes that are sometimes elaborated. In such an endeavor, we must be familiar with and apply a method that is scientific in its spirit of inquiry based on checking, confronting, even doubting what appears certain to others, and historical in the sense that predominant periods and large syntheses must be identified, and that creative men must not be separated from their surroundings, or from the prevailing ideas and events of their time.-andrk CouR- NAND, M.D. Circulation of the Blood. Edited by Alfred P. Fishman, M.D., and Dickinson W. Richards, New York, Oxford University Press, 1964, p. 3.