observations on digitalis intoxication—a plea

POSTGRAD. MED. J. (1964), 40, 628

OBSERVATIONS ON DIGITALIS INTOXICATION-A PLEA

A. SCHOTT, M.D. (Heidelberg), M.R.C.S.Hon. Consulting Cardiologist, Queen Mary's Hospital For the East End, London, E.15.

I will not give a fatal draught to anyone if I amasked, nor will I suggest any such thing.

From the Hippocratic Oath.Seldom a day elapses that we do not encounter

either minor or major evidence of digitalis over-dosage. Such experience has led a member of thehouse staff of the Peter Bent Brigham Hospital toremark that nowadays lanatoside is replacinghomicide as a leading cause of death.

Bernard Lown, 1957.

IN the course of routine reporting on electro-cardiograms recorded in a hospital groupincreasing apprehension was felt about thehigh incidence of tracings suggesting digitalisintoxication. Two thousand consecutive ECGs,recorded within about six months in 1962 andsent for reporting, were therefore analysed and,as briefly mentioned (Schott, 1964), 597 trac-ings referred to 348 patients who had digitaliswithin the fortnight preceding at least oneECG. On a preliminary study, ECGs witharrhythmias highly suggestive of overdigitaliza-tion were found in at least 10% of the 348patients. The present paper reports the moredetailed analysis of these records.The fact that this study was made in a

Group electrocardiographic department hadthe advantage that the recording, carried outby trained technicians, and the reporting, doneby one observer. were uniform. Furthermore,the patients whose ECGs were sent representedan unselected cross-section of in- and out-patients, mostly medical, but also includingsurgical and obstetric cases. They were underthe care of different consultants and looked afterby various registrars and house physicians, andoutside by different general practitioners, withconsiderable variations in experience in digi-talis dosage. The present observations maytherefore well be acceptable as an example ofconditions prevailing in certain non-teachinghospitals and general practices. This set-uphad the disadvantage that only a small minorityof the patients was under the care of thereporting physician, who was given the essen-tial clinical data on tihe request form (repro-duced in Schott and SWI1, 1963), but was

unable in the majority of cases to correlate theECGs with all the clinical features or to follow-up further developments by personal observa-tion- of the patients. The system also accountsfor the fact that in some cases the number ofECGs is inadequate as further tracings, whichwould have been desirable, were not requested.

ResultsFrom Table 1 it will be seen that digitalis

over-dosage was suspected on ECG groundsin 42 of the 348 patients, an incidence of 12%.In 2 cases the part played by digitalis wasconsidered doubtful; if these are disregarded(Nos. 37 and 42), the incidence would be1 1.5 /0.There were 19 males and 23 females. The

age distribution is shown in Fig. 1, from whichit is seen that the majority of patients wereelderly: 33 (78%0) were over 61 (16 males(84%) and 17 females (74%/O)), and 22 (52%)were over 71 (12 males (63%) and 8 females(34%)).A diagnosis of suspected digitalis intoxica-

tion was based on the following arrhythmias:Ventricular ectopic arrhythmias in the

presence of a basic sinus rhythm ... 7 casesAtrial fibrillation with high-grade partial

or complete A-V block or A-V tachy-cardia, without extrasystoles ... ... 8 cases

Atrial fibrillation with extrasystoles andhigh-grade partial or complete A-V block 8 cases

Atrial fibrillation with extrasystoles withouthigh-grade partial or complete A-V block 6 cases

Paroxysmal atrial tachycardia with A-Vblock ... ... ... 4 cases

Mainly atrial arrhythmias other thanparoxysmal atrial tachycardia with A-Vblock ... ... ... ... ... 4 cases

Complex arrhythmias (3 with A-Vdissociation) ... ... ... ... ... 4 cases

Second degree A-V block (doubtfulregarding digitalis toxicity) ... ... 1 caseAll these arrhythmias have been established

as manifestations of digitalis toxicity. It hasbeen stated by several authors that digitaliscan cause practically every known arrhythmia(Diefenibach and Meneely, 1948/9; Lown andLevine, 1954; Pick, 1957; Spang, 1957; Fried-

November, 1964 SCHOTT: Obsetrvations on Digitalis Initoxic(ationi 629

50- L TOTAL 50 U MALES

L FEMALES

40- 40-

30 -30-

20- 20-

10I .*...

4-0 51-60 61-0 780 81-87 45-50 5 1-60 61I-70 71-80 81-87AGE GROUP AGE GROUP

Fic;. 1.-Percentage age distribution of the 42 patients.

berg and Donoso, 1960; Lown, Wyatt andLevine, 1960; Schwiegk and Jahrmnirker, 1960;Schoen and Schroder, 1962). While theincidence of particular arrhythmias as given invarious publications differs, an ever increasingnumber of them has been established as fre-quently due to, or precipitated by, the drug.Regarding the recent past, this holds good par-ticularly for atrial (Lown and Levine, 1954,1958; Lown and others, 1960; Oram, Resnekovand Davies, 1960; Harris, Julian and Oliver,1960; Burton, 1962; Hunziker, Schaub andHolzmann, 1964) and A-V (Pick andDominguez, 1957) tachycardias, and A-V dis-sociation (Friedberg and others, 1960; Schott,1960; Soffer, 1961: Jacobs, Donoso and Fried-berg, 1961). Obviously, the converse is alsotrue: practically all abnormal rhythms seenin overdigitalized patients may occur withoutdigitalis or any other drug. However, if sucharrhythnmias occur in the course of digitalistreatment it is appropriate to consider them aspossible, and in many cases probable, mani-festations of digitalis toxicity. Those recordedin the present series, with the exception of

Case 42 (second dearee A-V block), areknown to occur almost exclusively in diseasedhearts, digitalis being a precipitating ratherthan the sole causative, though therefore noless dangerous a factor. In the series underreview, 13 patients (31/ ) died within a shortperiod after the last ECG, at a time when thedrug must still have been active, vii. 7 of 19males (37>/ ) and 6 of 23 females (261/ ).(Nos. 1, 2. 5, 9, 16, 18. 26, 27, 28, 31, 33, 38,42). In 9 (211/,>) death was considered to havebeen directly due to, or at least accelerated by,digitalis, (numbers of these cases in italics).and in one further case (No. 28) this seemedprobable.

DiscussionThe inicidenice of about 12 found in this

series, while disturbingly high, comparesfavourably with that reported by others as15 /, (Giuffra and Tseng, 1952) and approx.200/., (Rodensky and Wasserman, 1961). Thereseems little doubt that it is on the increase,paradoxically since the introduction of pure

POSTGRADUATE MEDICAL JOURNAL November, 1964

TABLE 1CLINICAL DETAILS OF 42 PATIENTS SUSPECTED OF DIGITALIS OVERDOSAGE

AES: Atrial extrasystoles. A.F.: Atrial fibrillation. AR: Atrial rate. C.C.F.: Congestive cardiac failure.ES: Extrasystoles. VES: Ventricular extrasystoles. VR: Ventricular rate.

Serial No.Sex Age Clinical Diagnosis Features of Arrhythmia

No.

Ventricular ectopic arrhythmias; basic rhythm sinus rhythm

DosageClinically

suspectedRemarks

1.F. 67,

30211

Anterior infarct Multiform yES, attimes bigeminy

2. Aortic incompetence VES, bigeminyM. 61, and stenosis. Angina

30316 pectoris. C.C.F.

3. Acute exacerbation Multiformn VES inMr 69, of chronic bronchitis series. Fig. 2a.

30523

4. Ischsemic h e a r t VES, bigeminy'M. 77, disease. Old infarcts.

30142 C.C.F.

5. C.C.F. B3roncho-M. 75, pneumonia. Anterior

30819 infarct.

6. Attacks of nocturnalM. 77, dyspnoea 6 months.

28797 Old post. infarcts.

7. Chronic bronchitis,M. 78, emphysema. Hyster-

30738 ical over-breathing.? anterior infarct.

On adm. was on dig. fol. gr.2 b.d. + neonaclex. Wasput on gr. I o.d. despiteclinically ? coupling. 3 dayslater dig. stopped in view ofECG. Died 4 days later "inspite of emergency digoxinand hydrocortisone."

Digoxin 0.25 mg. b.d.mersalyl, hydrosaluric K.Bigeminy after 10 days. Dig.stopped for 48 hours, re-sumed o.d., also hydro-saluric K 3 days a week.After 10 days sinus tachy-cardia of 100.

Digoxin 1.25 mg. in 18hours, then stopped. 5 dayslater only single uniformVES after every 3 or moresinus beats.

On adm. Digoxin 0.5 mg.six-hourly x 3, then 0.25 mg.t.d.s. for 2 days: 3.0 mg. in3 days (minimum).

Ectopic ventricular 1.5 mg. Digoxin i.m. in 24tachycardia. T h e n hours (i.e. 0.5 mg. stat, thenA.F. with ES -4-- six-hourly). Then stopped.

and periods of Procaine amide oral 500bigeminy in 2 ECGs. mg., repeated after 3 hours,

+ 250 mg. after 6 hours,then 250 mg. six-hourly for5 days, then b.d. for 1 week,then stopped. Digoxin re-started after 4 days, i.e.0.25 mg. t.d.s. for 3 days,b.d. for next 9 days, o.d.following day. Also hydro-saluric, mersalyl, potassiumsupplement.

10 days after admis- On adm.: Digoxin 0.25 mg.sion: Bigeminy in 3 t.d.s. for 2 days, then b.d.and part of a fourth 7 days. Stopped because oflead. 1 week before coupling. 5 days later 'pulseonly occasional VES. regular', digoxin restarted

0.25 mg. b.d. 1 week later'ES', digoxin stopped 2 days,then restarted; 2 days latercoupling, digoxin reduced toI tablet b.d. Discharged on0.25 o.d.

Numerous multiform On adm.: Digoxin 0.5 mg.VES, at times two in stat, then 0.25 mg. six-succession. Also a hourly till pulse below 75.few AES. No record of total amount.

Stopped 6 days after admis-sion. Discharged fortnightlater without digitalis.

Yes, becauseof coupling

onadmission

Yes, becauseof nausea

andcoupling.

Should not have been put ondigitalis without ascertainingprevious medication. "Emer-gency digoxin" suggests un-awareness of digitalis intoxi-cation manifesting itself asdeterioration of cardiac con-dition. Overdigitalization as-sumed to have precipitateddeath.

Overdigitalization o b v i o u ssince bigeminy appeared onlyafter digitalization. Digitalistoxicity increased by diuretics.Drug stopped for far tooshort a time. Patient died 6weeks after admission frompulmonary embolism.

No Stated on request form thatpatient never had digitalis.Questioning revealed thelarge dose.

No Dose too high, particularlyin view of patient's age.

No Overdigitalization both ini-tially a n d subsequently.Digitalis toxicity increasedby diuretics, procaine amideand infarct. Died 8 days afterlast dose of digoxin. Digita-lis assumed to have precipi-tated death.

Yes No information was obtainedabout digitalis medicationbefore admission. ECG de-velopment typical of over-digitalization. Time of stop-ping too short. Dose on dis-charge likely to be too highin view of observation inhospital.

No Digitalis given withoutindication. Wrong method todetermine digitalis dose.

Atrial fibrillation with high-degree or complete A-V block or A-V tachycardia without extrasystolos

8. Mitral stenosis and Complete A-V block, Had been on digoxin 0.25F. 57, incompetence. Dia- ventricular rate 38. mg. t.d.s. for unspecified

30579 betes. duration, also on diuretics.Continued on digoxin 0.25mg. t.d.s.

No Warning contained in ECGdisregarded.

630

SCHOTT: Observations on Digitalis Intoxication

Serial No. CiialSex Age Clinical Diagnosis Features of Arrhythmia Dosage Clinically

No. suspectedAtrial fibrillation with high-degree or complete A-V block or A-V tachycardia without extrasystolos

9. Ischa2mic h e a r t A-V tachycardia of No record about digitalis NoF. 73, disease. C.C.F. 150, later A.F. Tran- before admission. On adm.

30221 sitional stage of sinus 0.5 mg. i.m. stat, then 0.25rhythm with many mg. t.d.s., after 3 days b.d.,mtultiform AES. -4- mersalyl 4- hydrosaluric

K. A.F. recorded 1 weekafter stopping digoxin.

631

Remarks

A-V tachycardia due tooverdigitalization, digitalistoxicity increased by con-current diuretics. A.F. pos-sibly also due to digitalisintoxication. Digitalizationstarted without prior ECGassessment of rhythm andcontinued despite ECG. Died11 days after digoxin wasstopped and 5 days afterA.F. was recorded. Deathassumed to have been pre-cipitated by digitalis.

10. Hypertension 270/130.F. 62, C.C.F.

29830

Complete A-V block,VR 57, later high-degree but no longercomplete A-V block.

11. Mitral incompetence. Complete A-V block.M. 81, C.C.F. VR. 46-50.

30633

12. Acute exacerbationF. 74, of chronic bronchitis.

30675 ? Left lower lobebroncho pneumonia.

Complete A-V block,VR 44.

13. Mitral and tricuspid In parts A-V block,F. 70, incompetence. Gross not quite complete.

30705 C.C.F. Ascites. Moderate A-V tachy-cardia, VR 80-90.

14. Ischemic h e a r t A-V tachycardia ofF. 74, disease. ? mitral 125.

30791 valvular disease.

15. Mitral incompetence.M. 59, C.C.F.

30474

Comolete A-V block.VR 55. In Lead aVLone cycle twice thelength of precedingand following ones.

Had been on digoxin 0.25mg. o.d. for 6 months.Changed to fol. gr. + o.d.six days after admission,and to gr. I on alternatedays a fortnight after adm.in view of second ECGstill showing signs of over-digitalization.

On "long term" digoxinb.d. (probably 0.25 mg.) andnavidrex K from G.P.Digoxin reduced to o.d.Navidrex K replaced bymersalyl. Also aminophyl-line.

G.P.'s letter: on dig. fol.gr. 1 b.d. and 2 tabletsesidrex K, no duration in-dicated. On adm. digoxin0.25 mg. t.d.s. No recordwhether or when digoxinstopped in view of ECG.About 1 month after ECGindicating overdigitalizationput on dig. fol. gr. 1 t.d.s.,discharged on that dose.

On dig. fol. gr. I b.d. "forsome time" by G.P. Stop-ped on adm. because ofslow pulse. Serum K 3.4mEq/l. Digitalis re-institutedabout 2 months later. Afteranother 4 months when ondigitalis and hydrosaluricECG showed the same con-dition.

No record of digitalis beforeadmission. On adm. digoxin0.5 mg. stat, then six-hourly0.25 mg. till apex rate below80, then 0.25 mg. b.d. Totaldose not ascertainable.

On adm. known to havebeen on "digitalis" tablets1 b.d. l diuretics. Onadm. put on digoxin 0.5mg. b.d. for the first 6 days;dose not stated for thefollowing 4 days, then on0.25 mg. b.d. for 1 week,and o.d. for the following6 days.

No Inadequate supervision out-side. Should not have beenput on digitalis without priorassessment of rhythm byECG.

No Inadequate supervision out-side. Digitalis medicationshould not have been con-tinued without prior ECG,assessment of rhythm, par-ticularly in view of low rate.

No No indication for digitalis.Although patient very ill onadmission, retching, vomit-ing and belching, was puton digoxin 0.25 mg. t.d.s.vith a diagnosis of gastritisand digitalis intoxication wasnot considered.

Yes Inadequate supervision out-side. Dose likely to be toohigh for maintenance, par-ticularly in view of patient'sage, and possibly of increas-ing severity of condition.

No Wrong method to determinedose. Dose too large forpatient of her age.

No Should not have been put ondigitalis on admission with-out prior ECG assessment ofcardiac condition, least of allon such a high dose.

Atrial fibrillation with extrasystoles and with high-degree partial or complete A-V block

16. Cor p u I m o n a 1 e, E-trasys'oles as bige- Had been on digoxin 0.25F. 60, heart failure. minial and trigeminal nig. b.d. for 2 months be-

28508 rhythm. fore admission. No digitaliswhile in hospital. FurtherECG 9 days after admissionshowed sinus rhythm.

Yes Inadequate supervision out-side. Died 10 days afteradmission. P.M.: Subacutecor pulmonale, organisingpuilmonary thrombi. Over-digitalization assumed tohave precipitated death.

November, 1964

632 POSTGRADUATE MEDICAL JOURNAL

Serial No.Sex Age Clinical Diagnosis Features of Arrhythmia Dosage

No.Atrial fibrillation with extrasystoles and with high-degree partial or complete A-V block

Clinically

suspected

November, 1964

Remarks

17. C.C.F. ChronicM. 84, bronchitis and em-

28853 physema.

18. Mitral incompetence.M. 71, C.C.F.

30701

On adm. multiformES. Abolished byprocaine amide. 17days later digoxin re-started, 0.25 mg. b.d.ECG 5 days later:coupled ES andventricular automaticbeats and completeA-V block, VR 88.

Numerous ES. VRvariable, with longintervals b e t w e e nsome beats, i.e. high-grade partial blockat times. Fig. 4a.

19 A o r t i c sclerosis, ES, at times bige-M. 73, chronic bronchitis, miny; periods of

30040 L L L pneumonia, ectopic ventricularB.P. about 250/105. rhythm.

20. Fresh myocardial ES, in one place 3M. 72, infarct. R and L in succession.

30703 ventricular failure.

21. Rhtumatic mitralF. 45, stenosis and incom-

30082 petence, a o r t i cstenosis, tricuspid in-competence.

Bigeminy due to ES.

22. Mitral stenosis and Bigeminy due to ES.F. 63, incompetence. Later complete A-V

28954 block, VR 75. Fig. 5.

Probably on digoxin 0.25mg. o.d. since last discharge,i.e. at least 6 months. Dig-oxin 0.25 mg. b.d. on adm.,stopped 12 days after adm.in view of first ECG. Re-started 0.25 mg. b.d. 5 dayslater; reduced to o.d. inview of second ECG anddischarged on that dose.Had also 'intensive diuretics+ supplementary K'.

No record of previous treat-ment. On adm. digoxin 0.5mg. stat., repeated oncesame day, then 0.25 q.i.d.till pulse rate below 80.No record of total dosegiven.

Before admission on tab.dig. b.d., no record forhow long. Continued asdigoxin, 0.25 mg. b.d.Stopped in view of ECG,restarted after 3 days withhalf the dose, i.e. oncedaily. Discharged on thatdose. No further ECG.

On adin. digoxin 0.5 mg.+ 0.25 6 hours later. 0.25mg. q.i.d. next day; b.d.following day; i.e. 2.25 mg.within 36 hours.

Seen one month before ad-mission as O.P. with bige-miny. No record of dosageat that time. On adm. hadnot had digitalis for at leasta fortnight and ECG showedonly 1 ES in whole record.Then put on digoxin 0.25o.d. which reduced VR to50-60. Comment by othercardiologist consulted aboutvalvotomy: "Large myocar-dial factor, watch digitalis."

No record about digitalisbefore admission. On adm.digoxin 0.5 mg. twice onfirst day, 0.25 t.d.s. follow-ing day, i.e. 1.75 mg. in48 hours. Stopped becauseof 'coupling'. On third day0.25 o.d., then b.d. forfollowing 6 days.

23. Hypertension, ar- At times bigeminyP Had been on "digitalis" be-F. 66, teriosclerotic heart due to ES, at other fore admission, but dose

28456 disease, mental in- times complete A-V could not be ascertained.stability. block. ECG on adm. see preceding

column. After 1 week inhospital without digitalis nosigns of overdigitalization.Discharged on digoxin 0.25mg. o.d. Three months laterseen as O.P., VR very muchlower, suggestive of impend-ing overdigitalization.

Should not have been put ondigitalis on admission with-out prior ECG assessment.Subsequently digitalis re-started too soon. Doses toohigh particularly in view ofpatient's age. Toxicity en-hanced by diuretics.

No Should not have been put ondigitalis without prior ECGassessment of cardiac condi-tion, particularly as pulse onadmission was below 80according to chart. Wrongmethod to determine digitalisdose. Pat. appeared to dowell but collapsed and diedsuddenly 5 days after ECG.No P.M. Death assumed tohave been due to, or pre-cipitated by, digoxin causingventricular fibrillation.

No Inadequate supervision out-side. Should not have beenput on digitalis without priorECG assessment of rhythm.Drug stopped for too shorta time. Further ECG shouldhave been requested to de-termine maintenance dose,particularly in view of age.Doubtful whether any in-dication for digitalis.

No Dose too high in view of ageand cardiac condition.

No A patient particularly sensi-tive to digitalis. Inadequatesupervision outside.

Yes, because Should not have been put onof coupling. digitalis without prior ECG

assessment of rhythm. Ini-tial digitalis dose too high,in view of possible previousdigitalis medication. Drugstopped for too short a time.Case illustrates two differentarrhythmias in same patientcaused by digitalis intoxica-tion.

- The patient's mental instabil-ity made it impossible toascertain how much digitalisshe was taking. She seemedto take the drug quite erra-tically. Significant that whenunder observation in hospitaland no digitalis had beentaken for 1 week signs ofprevious overdigitalizationhad disappeared.

November, 1964 SCHOTT: Observations on Digitalis Intoxication

Serial No.Sex Age Clinical Diagnosis Features of Arrhythmia Dosage

No.

Atrial fibrillation with extrasystoles and with high-degree partial or complete A-V block

24. Left ventricular fail- ES in varying num-F. 75, ure. bers and periods of

20683 bigeminy.

25. Mitral stenosis and Multiformii ES, atF. 63, incompetence, times bigeminy.

28616 C.C.F.

26. ? Carcinoma of ECG on adm.: A.F.,F. 67, bronchus. high VR; ECG fort-

29899 ?? Myocardial in- night after adm.: VRfarct. much lower, bige-

miny due to multi-form ES.

27. Ischamic h e a r t Multiform ES.F. 76, disease.

30365

28. Cerebrovascular ac- Low ventricular rate,M. 85, cident. Prepare for multiform ES (ECG

29732 prostatic surgery. 1 week after admis-sion).

29. Mitral stenosis, car-F. 49, cinoma cervix.

29212

Appearance of ESused to determineoptimum dose ofdigitalis as patientvery difficult tostabilise.

Had been on digoxin 0.25q.i.d. for 2 days beforeemergency admission. Onadm. 0.25 mg. b.d. for 1day, then o.d. First ECG1 day after adm.: occasionalES. Second ECG 4 dayslater: numerous ES withperiods of bigeminy.Before admission on digoxin0.25 mg. b.d. for unspecifiedperiod. Overdigitalized onadmission. Digitalis with-held for 11 days, then re-started o.d. No furtherECG. On adm., accordingto case note, 'triple rhythm',nausea, vomiting.No record of digitalis beforeadm. in G.P.'s letter. Onadm. digoxin 0.5 mg. i.m.repeated six-hourly 3 times,then 0.25 oral t.d.s. till apexrate below 90, then b.d.Had 4.25 mg. in 4 days.Omitted after 4 days, butonly for 2 days, then re-started with half the dose,i.e. o.d. Second ECG 6 daysafter restarting.

G.P.'s letter: C.C.F. forsome weeks, on digoxin tab.1 t.d.s. -4- saluric tab. 1t.d.s. on alternate days. Onday after adm.: digoxin 0.5mg. i.m., further 0.5 mg.same day oral, then 0.25mg. t.d.s. Two days afteradm. also 0.25 mg. i.m."for very fast pulse". Oralmedication apparently con-tinued until pat. died 2 dayslater ("irregular apex beat,rate about 120").On adm.: digoxin 0.25 mg.q.i.d. for 3 days, then b.d.for 10 days. Then stoppedfor 2 days, restarted o.d.Died suddenly 1 monthlater.

Digoxin 0.25 mg. o.d. andb.d. on alternate days foundto be optimum maintenancedose despite causing 12 ESin 12-lead record. Whenaccidentally without digoxinfor 3 days VR 144; whencontrolled VR about 84.

No Dosage too high for patientof her age.

- Inadequate supervision out-side. Overdigitalization shownby ECG recorded day afteradmission.

No Doubtful whether any indica-tion for digitalis. No ap-parent indication for parent-eral route. Gross overdosage,particularly in view of age.Wrong method to assessdosage. Stopped for too shorta time. Pat. died about 1month after last ECG withlung abscess; ? carcinoma.

No Should not have been put ondigitalis without prior ECGassessment of rhythm. Grossoverdigitalization, particular-ly in view of age. Wrongmethod to judge conditionand determine dosage bypulse or heart rate. Over-digitalization not recognisedas aggravating failure. Deathassumed to have been dueto digitalis intoxication.

No Initial dose too high particu-larly in view of age. ECGrequested much later thanadvisable. Drug stopped fortoo short a time. Cause ofsudden death unknown; digi-talis as contributory causepossible.

- Appearance of ES used todetermine optimum mainten-ance dose.

Paroxysmal atrial tachycardia with A-V block

30. C o r pulmonale, PAT of 125-150 withM. 75, chronic bronchitis. varying A-V block,

29509 Old pulmonary T.B. at other times sinustachycardia with VESand numerous AES.

31. Ischaemic h e a r t PAT, AR 214, 2:1F. 72, disease. C.C.F. A-V block.

29837

On adm.: Dig. fol. grs., 3t.d.s. first day; grs. 2 t.d.s.second day; gr. 1 t.d.s. thirdday, i.e. grs. 18 = about 3mg. digoxin within first 3days. Then gr. 1 b.d. for 3Jweeks, stopped for 6 days,restarted gr. + b.d. On oraldiuretics throughout.

Had been digitalized byG.P. with digoxin, 0.25 mg.t.d.s. Began to vomit on 4thday, but G.P. reassured her(from G.P.'s letter). Sent toO.P. on (probably) 6th dayof digoxin treatment andwas admitted. On adm. puton dig. fol. gr. I t.d.s. Stop-ped 2 days later. Patientdied 2 days later.

No Gross overdosage initially aswell as subsequently. Drugstopped for too short a time.Inadequate attention to ECGwarning.

No Failure to recognise symp-tom of digitalis intoxicationoutside. Should not havebeen put on digitalis onadmission. Death assumeddue to digitalis intoxication.

Clinicallysuspected

633

Remarks

POSTGRADUATE MEDICAL JOURNAL November, 1964


No.

Paroxysmal atrial tachycardia with A-V block32. Septum primum de- Right bundle branch

M. 49, fect; block. PAT, AR 250,30317 ? comm on A-V varying A-V block.

canal.

33. Ischxmic h e a r tF. 63, disease. C.C.F.

29289

Second degree A-Vblock (3 2). Twodays later PAT, AR300, 2: 1 A-V block.Fig. 3.

Dosage

On digoxin 0.25 mg. b.d.and quinidine sulph. grs. 3t.d.s. for at least a year +most of the time hydrosalu-ric K 1 tab. 5 days a week.Digoxin 0.25 mg. b.d. con-tinued throughout stay inhospital.

On adm.: digoxin 0.75 mg.stat., then four-hourly. 0.25mg. b.d. on following 3days. Then 0.25 mg. eight-hourly for 1 day, b.d. fol-lowing day, then stopped.Second degree A-V block re-corded 1 week after adm.,PAT 2 days later. Patientdied the following day.

Clinicallysuspected

Remarks

No Obvious overdigitalization.In case note after last dis-charge: "In view of his ECGreport" (tracing arrived afterdischarge) "it would beworth while reducing hisdigoxin to 0.25 mg. o.d. untilseen in the O.P. Clinic." Butformer dose was repeatedwhen he was next seen.

No Obvious overdigitalization.3:2 A-V block considered byH.P. as "pulsus bigeminus",which suggests confusionwith ES. Death assumed tohave been due to digitalisintoxication.

Mainly or solely atrial arrhythmias other than paroxysmal atrial tachycardia with A-V block

34. Syphilitic aortic in- Left bundle branch Had been on digoxin 0.25F. 77, competence, C.C.F. b o c k. Numerous mg. o.d. for nearly two29694 AES, often occurring years. At the time of ECGin series. Periods of was also on hydrosaluric K.a t r i a 1 tachycardiawithout A-V blockof about 176, alsoVES. Later A.F.Fig. 2b.

35. History of attacksF. 64, of paroxysmal tachy-

30009 cardia.Hysterectomy.Anterior i n f a r c twhile in hospital.

36. C o r pulmonale,M. 57, acute exacerbation

30421 of chronic bron-chitis.

37. Acute exacerbationF. 79, of chronic bron-

30677 chitis. C.C.F.

Complex arrhylhmlas

38. Chronic bronchitisM. 71, and emphysema.

29162 C.C.F. Old anteriorinfarct.

"Extrasystolie a par- Digoxin 1 mg. stat., thenoxysmes tachycardi- 0.5 mg. q.i.d., then 0.25ques" (repetitive par- mg., q.i.d., i.e. 4 mg.oxysmal tachycardia). digoxin in 48 hours. Sub-One day later A-V sequently 0.25 o.d. fortachycardia of 150 (probably) 9 days (no exactwhich changed into record about duration).sinus rhythm laterthat day. Fig. 6.

Changes in P waves. Had been on digoxin 0.25mg. b.d. since last discharge7 months and 3 weeks be-fore readmission. Samemedication continued. ECG3 days after readm.: noevidence of digitalis intoxi-cation. 5 days later digoxinreduced to 0.25 mg. o.d. be-cause of nausea. ECGfortnight later showed mark-ed changes in P waves at-tributed to digitalis. Fur-ther changes in ECG 5 dayslater. Five weeks after re-duction of dose P waves hadreverted to normal.

Very numerous AES. Dig. fol. grs. 2 t.d.s., nextChanges in P waves day gr. 1 t.d.s. After thatcompared with ECG gr. 1 b.d. Overdigitalization5 years previously suggested by ECG whenwhen patient was not patient had grs. 15=abouton digitalis. 2.5 mg. digoxin. Dose sub-

sequently reduced to gr. 1daily.

Atrial tachycardia of Had been discharged on dig-about 300. A-V dis- oxin 2 years before re-sociation. A-V tachy- admission; no record aboutcardia of 88. Multi- dosage during that time. Onform VES. Fig. 4b. adm.: 0.25 mg. b.d. for 4

days, stopped (in view ofECG) for 3 days, then o.d.for 1 week. ECG againmultiform VES, fewer nextday. Patient died 3 daysafter last ECG.

Yes, because Very great improvement onof nausea stopping digitalis. This con-

firmed the view that thearrhythmia was due to thedrug. This observation illus-trates the toxic effect of asmall dose given over longperiod in an elderly patient.VR during the later A.F.was controlled by digoxin0.25 mg. twice weekly.

No Gross overdosage resulted atfirst in "Extrasystolie Aparoxysmes tachycardiques"and then in A-V tachycardia.Reversion to sinus rhythmon stopping the drug. ECGsigns of infarct with +serology developed 8 daysafter the end of the arrhyth-mias; ? arrhythmias precipit-ated infarct.

Yes The occurrence of nauseaand the changes in P wavesindicated that the long con-tinued medication with dig-oxin 0.25 mg. b.d. hadresulted in intoxication.Reduction to half the doseresulted in reversion of Pwaves to normal within 5weeks. Drug should havebeen stopped instead ofreduced at appearance ofsymptoms and signs of in-toxication, if there was anyindication for it which seemsdoubtful.

No Overdigitalization suspectedby atrial arrhythmia, also inview of large dose for age.This case cannot be consi-dered as more than probableas no further ECGs weretaken. Progress appears tohave been satisfactory on thesmaller dose.

No Inadequate supervision out-side of hospital. Should nothave been put on digitalison admission without priorECG assessment. Drug stop-ped for too short a time.Death assumed to have beenprecipitated by digitalisintoxication.

634

I

November, 1964 SCHOTT: Observations on Digitalis Intoxication


No.

Complex arrhythmias

39. Acute C.C.F.F. 56,

28723

40.M. 87,

29867

C.C.F.

Two days after ad-mission and initialdigitalization: sinusrhythm with bige-miny due to VES,also periods of ecto-pic atrial rhythm.ECG 12 days later:much shorter periodsof bigeminy, stillsuggestive of over-digitalization.

Before digitalis: sinusrhythm, rate 90, 1AES and 2 VES inwhole ECG. Afterdigitalis and whiile onmersalyl, 3 days afterprevious ECG: Sinustachycardia of 115,more AES. Next dayd u a 1 tachycardia:atrial of 214, A-Vof 136 dissociationw i t h interference,Fig. 7. Next dayatrial tachycardia of176 with 1: 1 con-duction. Next 3 ECUson following 4 days:s i n u s tachycardiawith decreasing num-ber of ES consistentwith waning digitaliseffect.

Digoxin 0.5 mg. stat., 0.25mg. six-hourly until apexrate below 80. No recordwhen digitalis was stopped.10 days after admission 0.25mg. b.d. for 2 days, theno.d. Second ECG 5 daysafter start of this treatment.Nine days later digoxin re-duced to 0.25 mg. 3 timesa week, with note 'perfectlywell controlled". Patient re-garded as "hypersensitive todigitalis" .

Not ascertainable as casenote misfiled in hospital andtemporarily not available.

No Although the exact dose ofdigoxin resulting in thearrhythmia is not known itis clear from subsequentdevelopment that only muchsmaller doses were requiredand the initial doses were toohigh. Also, wrong method todetermine optimum dose fromapex rate.

No The occurrence of the arrhy-thmia during digitalis treat-ment and its waning afterreports on overdigitalizationcannot leave any reasonabledoubt that the arrhythmiaindicated digitalis intoxica-tion.

41. Mitral incompetence,F. 60, thyrotoxicosis.

29115

Second degree A-V block42. Chronic bronchitis

M. 72, and emphysema.29060 Status asthmaticus.

L. pneumothorax.

During a previous admission, when patient was inhospital for 2 months, difficult to stabilise. Dis-clsarged on lanatoside C 0.25 m.g. q.i.d. andneomercazole 10 mg. t.d.s., although ECG I weekbefore discharge showed AF with VR of 140 andfairly frequent ES, and caution re digitalis hadbeen recommended. On emergency readmission 2,2months later put on digitoxin 0.1 mg. t.d.s. +quinidine sulpi. grs. 3 t.d.s., also hydrosaluricK 100 mg. on alternate days. ECG on day afteradmission showed in some parts bigeminal rhythmdue to VES, in other parts A-V dissociation (Fig.8). Serum K = 3.3 mEq/ 1. Extra K given; serumK next day 4.9 mEq/l. Digitoxin and quinidinestopped. 4 days later ECG showed first degreeA-V block, P-R 0.24 sec. Quinidine grs. 3 t.d.s.restarted the day before, and digitoxin 0.1 mg.b.d. the day after ECG was recorded. One weeklater digitoxin reduced to 0.1 mg. o.d.

First ECG: First andsecond degree A-Vblock. Second ECG8 days later and 1week after digoxinwas stopped: onlyfirst degree A-Vblock.

On "digitalis" b.d. by G.P.for unspecified duration be-fore admission. Also onhydrosaluric K 50 mg. aday 4 days a week forlong periods. On adm. puton digoxin 0.25 mg. b.d.continued for 5 months and8 days, possibly with oc-casional breaks the durationof which cannot be ascer-tained from the notes. Onthe day before stoppingdigoxin patient had an at-tack of crushing retrosternalpain and hypotension. ECGshowing first and seconddegree A-V block was takenon the day following thisattack and on the first daypatient was without digitalis.11 days later digoxin re-started with 0.25 mg. o.d.,increased to b.d. 2 dayslater. Patient died the fol-lowing day.

No It seems likely though notcertain that this patient hadbeen on lanatoside C 0.25mg. q.i.d. for the 2- nsonthspreceding readmission; in anycase, this dose was too higls,particularly in view of ECGwarning and previous experi-ence of difficulties in stabilis-ing. Digitoxin particularlyunsuitable in this patient. Theconcurrent medication withquinidine and hydrosaluric Kincreased tendency to arrhyth-mias due to digitalis toxicity.Quinidine and digitalisrestarted too soon. ECGincreased tendency to arrhyth-mias in different parts of thesame tracing, and a furtherECG a third manifestation(first degree A-V block) duringwaning digitalis intoxication.

No Patient died 16 days after theattack. No P.M. The attackwas thought to have beenmyocardial infarction al-though all tests were negativeexcept S.L.D. 650 units onthe day following the attack.In this patient the arrhyth-mia can only be consideredas probably due to, or aggra-vated by, the long continuedexhibition of digoxin 0.25mg. b.d., particularly in viewof patient's age. The occur-rence of the arrhythmia andsubsequent subsidence wouldbe consistent with a waningdigitalis effect, but may alsohave resulted from an infarctin which case digitalis islikely to have been an ag-gravating factor.

DosageClinically

suspected

635

Remarks

POSTGRADUATE MEDICAL JOURNAL

glycosides from which the reverse was expec-ted (Lown and Levine, 1954; Levine, 1955).The mortality of 21% is higher than thatreported as 11% by Rodensky and Wasserman(88 patients), 4% by Von Capeller, Copelandand Stern (148), 6.6% by Flaxman (30), and4.5% by Moody (44), but lower than theaverage reported by Dreifus, McKnight, Katzand Likoff in old people where it was 11% inpassive nodal rhythm, 35% in paroxysmalatrial tachycardia with block, 42% in activenodal rhythm and 68% in ventricular tachy-cardia. This comparison emphasizes theimportance of age.

Dreifus's statement: "The most significantpredisposing factor in the development ofdigitalis toxicity was inappropriate administra-tion" is unquestionably applicable to thepresent observations, the following points deser-ving special consideration as having been largelyresponsible:

AgeDespite some contrary statements in the

literature that the patient's age is of little orno importance (Moody, 1951; Schwiegk andJahrmarker, 1960; Rodensky and others,1961), there is no doubt of the overwhelmingevidence that old people are more susceptibleto the drug than younger ones (Raisbeck,1952; DeGraff, 1954; Kay, 1955; Wollheim,1954/55; Crouch, Herrmann and Hejtmancik,1956; Shrager, 1957; Scherf, 1958; VonCapeller and others, 1959; Lown and others,1960; Soffer, 1961; Goldberger, 1962; Holz-mann, 1962; Dreifus and others, 1963). More-over, the more advanced the myocardialchanges the narrower the boundary betweentherapeutic and toxic doses, whereby the con-siderable variations in the optimum dosebetween different patients, and in the samepatient at different times, increase the difficul-ties in the management of these cases, necessi-tating greater individualization of treatmentand far closer supervision than is oftenaccorded to them (see below).A perusal of the dosages and their effect on

the ECG. as listed in Table 1, leaves no doubtabout their having been excessive in anappreciable proportion of the cases. Further-more, it should be borne in mind that dosesconsidered as 'average' tend to be too highfor patients in these age groups.

Exhibition of Digitalis without IndicationSome patients are given digitalis without

indication, common causes being a diagnosis

of 'heart failure' on inadequate grounds, inparticular on the strength of some basal ralesonly, or by mistaking dyspnoea due to pul-monary disease as being cardiac in origin(Levine, 1955). Such considerations seem toapply particularly to Cases 7, 12, 19, 26, 36and possibly 42 of the present series. Otherconditions, cardiac and non-cardiac, wherepatients were given digitalis without indica-tion, were discussed by Broome and Orgain(1946) and Burwell and Hendrix (1950). Insome cases the drug is given parenterallywithout any apparent reason.

Premature Start of Digitalization in HospitalIn the majority of cases where a diagnosis

of congestive heart failure was made, digitali-zation was started on admission withoutallowing any time for the effect of rest andnursing to become manifest. Furthermore,diuretics were often given concurrently whereperusal of the case notes failed to show anyindication for such drastic immediate treat-ment. The effect on electrolytes of diuretics,mercurial as well as thiazides, in aggra atingthe toxic action of digitalis is too well knownto merit any discussion, except for re-statingthat this combination, frequently used in con-temporary treatment, is one of the mostimportant factors accounting for the increasein the incidence of digitalis intoxication. Inthis connexion a normal serum K concentra-tion seems often to be considered an indicationthat further digitalis medication is safe,although it has been established with certaintythat such normal figures do not provide anyinformation about the intracellular K concen-tration or the intra-extracellular gradient,which in the present context are alone ofsignificance in respect of K depletion.A further source of error is the initiation of

digitalis treatment on admission without ascer-taining whether the patient had recentlyreceived the drug outside, or how much. Evena patient with obvious symptoms and/or signsof digitalis toxicity may be put on the drug onadmission (e.g. Cases 12, 15, 17, 19). Topostpone digitallis treatment until an ECG isavailable, which should be requested as a matterof routine on admission of elderly patients withcardiac disease, is clearly the method of choicein order to avoid this risk of overdosage, withthe possible exception of those very few patientsin whom immediate digitallization is mandatoryand who are known with certainty not to beunder the influence of the drug on admission.The importance of ascertaining the cardiac con-

636 November, 1964

November, 1964 SCHOTT: Observations on Digitalis Intoxication 637

~... ..

I~.-

...........(b). -

.........................................................

FIG. 2.-(a) Case 3. Lead aVL. After 1.25 mg. digoxin in 18 hours. Numerous multiformectopic ventricular beats.(b) Case 34. Lead aVL. After digoxin 0.25 mg. daily for nearly two years. Five atrialextra-systoles in succession followed by three sinus beats the first of which with anabnormal P wave. The last sinus beat is followed by a single atrial extrasystole; thepostextrasystolic interval is terminated by a ventricular ectopic beat, followed by twoatrial ectopic beats.

dition electrocardiographically before startingdigitalization is enhanced by the fact thatpotentially dangerous arrhythmias due to, oraggravated by, the drug are often present with-out any of the usual symptoms, such asanorexia, nausea, vomiting or visual disturb-ances (Herrmann, Decherd and McKinley,1944; Flaxman, 1948; Master, 1948, 1950;Gootnik, 1949; Moody, 1951; Cohen, 1952;Crouch and others, 1956; Shrager, 1957; VonCapeller and others, 1959; Schwiegk andothers, 1960; Soffer, 1961; Goldberger, 1962;Holzmann, 1962). This is borne out by thepresent observations which show that over-digitalization was clinically suspected in onlya small minority of the patients.

Mistaken Methods for Determining DigitalisDosage Clinically by the Ventricular Rate;Misinterpretation of Cardiac RhythmsThe mistaken belief that an optimum dose of

digitalis must reduce the ventricular rate inevery case seems still prevalent. As far aspatients with sinus rhythm are concerned thisis a misapplication of the condition prevailingin those with atrial fibrillation and a high ven-tricular rate. In patients with sinus rhythmthe drug either does not reduce the rate at allor only slightly, any effect on rate beingclinically irrelevant. Overdosage in suchpatients may result in ectopic ventricular

(Fig. 2a) or less commonly atrial (Fig. 2b)arrhythmias, which may be misdiagnosed asatrial fibrillation; or it may produce paroxys-mal atrial tachycardia with A-V block (Fig.3c), likely to be mistaken for sinus tachycardiaif the block is constant (it often is 2: 1), oratrial fibrillation if the block is variable. Asa result more digitalis is often given. Whilemany physicians are familiar with thesearrhythmias as manifestations of digitalistoxicity, it does not seem to be so commonlyappreciated that changes in P waves may bethe first sign of impending digitalis over-dosage, heralding paroxysmal atrial tachycardiawith 'block if medication is continued (Fig. 3c).

In atrial fibrillation a similar mistake isalso often made. The aim of digitalization insuch cases with a high ventricular rate is, ofcourse, to reduce this rate by increasing A-Vblock. If the ventricular rate does not dropsatisfactorily or even increases in the courseof the exhibition of the drug, dosage isincreased without considering the possibilitythat the rapid ventricular action may be dueto ventricular ectopic beats due to digitalisintoxication (Fig. 4). A further source of erroroccurs in patients with atrial fibrillation andirregular ventricular action in whom theventricular rhythm becomes regular duringdigitalization as a result of complete A-V blockwith regular A-V rhythm (Fig. 5b) or non-

638 POSTGRADUATE MEDICAL JOURNAL November, 1964

*-...

...44. 4........44,44 ..44 4 4 ~ 4 4 4~

...4..4..............~

4 14.4.44 44 4 ~ .4~. 444

FIG. 3.-Case 33. Lead II. (a) After (at least) 5.25 mg. digoxin within 5 days from admission:Sinus rhythm, rate about .82, digitalis effect. (b) One day after (a) during which a further0.5 mg. had been given: second degree (3:2) A-V block. (c) Two days after (b) duringwhich a further 1.25 mg. had been given, a total of 7 mg. in 8 days. Upper strip Lead Il:changes in P waves indicative of an ectopic atrial pacemaker taking over; lower stripLead V, of the same record: Paroxysmal atrial tachycardia with 2:1 A-V block, atrialabout 300.

..L..


l14

I lI:: ..-..

.::: ::: :: :::~~~~~~~ :. ..::::;::::::.. -:::;.:.:: .: .:.::....:.:..... ... ..; ........

............

.... ;......... ............. ... ;;. ...... .... .......

.............

....... ,..r.

.....

-

..) ..

FIG. 5.-Case 22. Atrial fibrillation. (a) Upper strip V5, lower strip V6 of the same tracingrecorded in immediate succession, after 1.75 mg. digoxin in 48 hours.V5: Bigeminal rhythm owing to a ventricular ectopic beat following every cQnducted one;V6: A-V tachycardia of about 107.(b) One week after (a) during which a further 2.25 mg. digoxin had been given.Lead III: Regular A-V rhythm, rate about 75.

paroxysmal A-V tachycardia (Fig. 5a), theregular rhythm being clinically misinterpretedas sinus rhythm or sinus tachycardia. Thus,the a:bnormal rhythm due to digitalis intoxica-tion is not recognised and digitalis medicationcontinued on the erroneous assumption thatrestoration of sinus rhythm had taken place.

FIG. 4.-(a) Case 18. Lead V5. Recorded two daysafter admission and massive digitalization.Atrial fibrillation, high-grade A-V block, extra-systoles.(b) Case 38, Lead V2. Had been put on digoxin0.25 mg. b.d. two years before readmission andwas still on the drug, possibly same amountthough exact dose could not be ascertained.Digoxin 0.25 mg. b.d. started on admission.Atrial tachycardia, A-V dissociation, ventricularectopic beats.

Not infrequently, one arrhythmia changesinto another, sometimes in the same ECG.Fig. 5 provides an example of atrial fibrilla-tion and regular A-V rhythm with andwithout extrasystoles, Fig. 6 one of twodifferent kinds of supraventricular arrhythmias.Figs. 7 and 8 illustrate various and at timesmore complex arrhythmias.

Unawareness that Digitalis Toxicity mayManifest itself as Refractory Heart Failure oras Increase in its Severity

Failure to recognise these possibilities islikely to induce the physician to give theoverdigitalised patient more digitalis, with theresult of further deterioration or even death.Cases 1 and 27 illustrate this sequence. Atten-tion to these manifestations of digitalis intoxica-


(

(a)

FIG 6.-Case 35. All strips Lead II. (a) The three strips are continuous. After 4 mg. digoxinin 48 hours, followed by 0.25 mg. once daily either for 2 days (total of 4.5 mg. in 4 days)or more likely for 9 days (total of 6.25 mg. in 11 days). Tracing recorded 11 days afterinitiation of digitalization. 'Extrasystolie a paroxysmes tachycardiques' (repetitive atrialparoxysmal tachycardia).(b) One day after (a): A-V tachycardia of about 150.(c) Later the same day as (b): Sinus rhythm, rate about 83.

....... ...-~ -c

,... .,...

RMS .

FIG. 7.-Case 40. Lead V1. The two strips are continuous. On digoxin, potassium andmersalyl. Atrial tachycardia of 206, A-V tachycardia of 115; dissociation with interference.

tion was drawn by Batterman and Gutner,(1950); Lown and Levine, (1954); Shrager,(1957); Von Capeller and others, (1959); Fried-berg and others, (1960); Soffer, (1961); especiallyto refractoriness by Kyser, (1955); Rodenskyand others, (1961).

Inadequate Action by the Physician in thePresence of Signs of IntoxicationEven if signs highly suggestive of digitalis

overdosage were reported from ECGs, somephysicians, disregarding the warning, continuedtreatment unchanged. Others reduced the dose,others again stopped it for a day or two, thatis, for entirely inadequate periods; even aweek is too short a time in many cases. Themethod of choice is to discontinue the drug,which suffices in many cases, re-instituting it insmaller doses at the appropriate time ifnecessary. In other cases the administration


r--.i;44. K 3vs 5i -KF:4p

4 S

FIG. 8.-Case 41. (a) Lead aVF; (b) V1, recorded in immediate succession. 21 months beforereadmission patient was discharged on lanatoside C, 0.25 mg. q.i.d., this dose havingpossibly been taken throughout the period. On admission put in digitoxin, 0.1 mg. t.d.s.+ quinidine sulph. grs. 3 t.d.s. + hydrosaluric K 100 mg. ECG taken on day followingadmission. aVF: A-V dissociation, atrial rate 88, manifest A-V rate 40, bigeminalventricular rhythm owing to a ventricular extrasystole following every A-V beat. V1:Nearly isorhythmic dissociation, atrial rate 88, A-V rate 83, slow shift of the two rhythms.The P wave last but three is a blocked AES resulting in shift of the atrial rhythm.

of potassium chloride, procaine amideor quinidine is required for the successfultreatment of these arrhythmias. How longdigitalis should be discontinued varies con-siderably in different patients and can only bedetermined by their close supervision.

Another mistake is to continue treatmentwith the same dose for longer periods withoutadequate clinical and particularly electro-cardiographic controls. This holds good forhospital out-patients as well as those under thecare of general practitioners.

Substituting one glycoside for another whichhad produced digitalis intoxication in thebelief that the replacement is less 'toxic', amethod adopted by some physicians, has nofoundation in fact. It has often been pointedout that every efficacious glycoside, whengiven in excess of the optimum dose for anindividual patient, produces toxicity the signsof which vary and often do so in the samepatient at different times. This view hasrecently been proved to be correct by a studyof Church, Schamroth, Schwartz and Marriott,(1962), who deliberately induced digitalisintoxication in 39 patients by three differentglycosides: digoxin, gitalin, and digitoxin, andconcluded: "When a patient was intoxicatedfor the second or later time, he was as likelyto show different manifestations as he was toshow the same; and this was independent of

whether the same or different glycosides wereused for the consecutive intoxications."ConclusionsThe main conclusion is to re-emphasize the

necessity of regarding the dosage of digitalisas an individual problem in every case. Dosesgiven in the literature as average ones forinitial and maintenance therapy can at best,be no more than very approximate guides. Itis the writer's firm belief that there is no suchthing as generally applicable average doses andin particular that those recommended as suchtend to be too high for elderly patients. Ifevery patient's requirements and tolerance ofthe drug are individually assessed and patientskept under adequate periodical control, smallerdoses of digitalis than often prescribed will befound sufficient to achieve the desired effectwithout producing intoxication. Thus, Szekelyand Wynne (1961) wrote: "A number ofpatients with advanced myocardial disease andatrial fibrillation who developed ventricularrhythms after conventional maintenance doses,have subsequently been maintained in a goodstate of compensation with satisfactory controlof the heart rate on very small doses ofdigitalis which did not produce toxic arrhyth-mias." These authors' efforts were so success-ful that, in a subsequent experimental andclinical study on digitalis-induced arrhythmias,they were only able to muster four patientsfor their purpose (Szekely and Wynne, 1963).


A PleaThese conclusions lead to a plea, directed to

those engaged in the teaching of under- andpostgraduates, to emphasize far more stronglythan, judging by the results, it has been donein the past, the necessity of individualizingthe dosage of digitalis in every patient, especiallyin elderly people, and of keeping patients underadequate periodical clinical and electrocardio-graphic control as long as they take the drug.The present observations, particularly whentaken in conjunction with the quoted publica-tions of others, leave no doubt that in practicethese considerations are not given anythinglike the attention they deserve.

SummaryAnalysis of 2,000 consecutive ECGs recorded

in a hospital group revealed 597 tracingsreferring to 348 patients who had had digitaliswithin a fortnight preceding at least one ECG.78% of the patients were over 61 and 52%over 71 years of age. Records highly sugges-tive of overdigitalization were found in 42

patients, an incidence of 12%. Thirteen patients(31%) died within a short period after thelast ECG, at a time when the drug must stillhave been active. In nine (21%) death wasconsidered to have been directly due to, orat least accelerated by, digitalis. The followingpoints are discussed as having been largelyresponsible: Disregard of the smaller toleranceand requirements of elderly patients; exhibi-tion of digitalis without indication; prematurestart of digitalization in hospital; mistakenmethods for determining digitalis dosageclinically; unawareness of digitalis toxicitymanifesting itself as refractory heart failure orincrease in its severity; inadequate action bythe physician in the presence of signs of in-toxication. As a conclusion it is re-emphasizedthat the optimum dose of digitalis must bedetermined individually in every patient, closesupervision being necessary throughout thetime the drug is taken. A plea is made tothose engaged in the teaching of under- andpostgraduates to stress these considerations farmore strongly than it appears to have beendone in the past.

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GOLDBERGER, E. (1962): The Changing Clinical Picture of Digitalis Intoxication, Amer. J. Cardiol., 9, 639.GOOTNIK, A. (1949): The Use of Digitalis, with Special Reference to its Toxicity, Veterans. Adm. med. Bull.,Series 10, No. 10-40, Vol. III, 1.HARRIS, E. A., JULIAN, D. G., and OLIVER, M. F. (1960): Atrial Tachycardia with Atrioventricular Block Dueto Digitalis Poisoning, Brit. med. J., ii, 1409.HERRMANN, G. R., DECHERD, G. M., and McKINLEY, W. F. (1944): Digitalis Poisoning, J. Amer. med. Ass., 126,760.HOLZMANN, M. (1962): Seltenere Arrhythmien insbesondere unter der Einwirkung von Digitalis, Schweiz. med.Wschr., 92, 721.HUNZIKER, A., SCHAUB, F., and HOLZMANN, M. (1964): Vorhoftachykardie mit A-V Block, Schweiz. med. Wschr.,94, 470.JACOBS, D. R., DONOSo, E., and FRIEDBERG, C. K. (1961): A-V Dissociation-A Relatively Frequent Arrhythmia,Medicine (Balt.), 40, 101.KAY, C. F. (1955): The Clinical Use of Digitalis Preparations, Circulation, 12, 116, 291. Pp. 298 seq.KYSER, F. A. (1955): The Role of Digitalis Intoxication in Refractory Heart Failure, Quart. Bull. North W.Univ. med. Sch. 29, 158.LEVINE, S. A. (1955): Pitfalls in the Care of Cardiacs, Ann. intern. Med., 42, 1270.LOWN, B. (1957): Potassium and Digitalis. In: Digitalis, ed. by E. Grey Dimond, p.166. Springfield Illinois:Charles C. Thomas.


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LOWN, B., and LEVINE, H. D. (1958): 'Atrial Arrhythmias, Digitalis and Potassium', New York: LandsbergerMedical Books.

LOWN, B., WYATr, N. F., and LEVINE, H. D. (1960): Paroxysmal Atrial Tachycardia with Block, Circulation,21, 129.

MASTER, A. M. (1948): Digitoxin Intoxication, J. Amer. med. Ass., 137, 531.MASTER, A. M., JAFFE, H. L., and DORRANCE, W. R. (1950): The Treatment of Heart Failure: Digitalis and

Mercurial Intoxication, Penicillin, Dicumarol, Major Surgery, N.Y. St. J. Med., 50, 553.MOODY, R. W., (1951): Maintenance Dose and Toxicity of Digitoxin, Ann. intern. Med., 34, 1349.ORAM, S., RESNEKOV, L., and DAVIES, P. (1960): Digitalis as a Cause of Paroxysmal Atrial Tachycardia with

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observations on digitalis intoxication—a plea

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