The treatment of digitalis toxicity

of By \V, A, Sot~t:M,~x A S C E N D E N C Y of digitalis ix~toxicatim'~ in recent )'ears has m a d e proMem an ever important clinical consideration in ~'V¢" r } patient receiving the drug. z l u c h of this increase is due t~ newer preparations amt forms of t r e a t m e n t ~ l n c h have a d d e d |:'a c"t ~( I' s" c,f imlmrt:mce tending Io prt> cipitate or p e r m i t subtle evolution of toxicity. A careful preventive appr~mch has b e c o m e essential. It must include: ( a ) the choice of p r o m p t l y excreted preparation~ in patients in wlmm surgical or e l e e k o l y t e manipulations seem likely, ( b ) use of minimal effective doses, ( c ) regular observation of the patient, ( d ) recognition by the patient as well as by the physician of the ~', M~nc~s of toxicib,, and ( e ) care in the use of p a r e n t e r a l preparations. All are f u n d a m e n t ,lq to the preventive aI~prcmch. All a r e i m p o r t a . t in active therapy. All will be discussed further below. E.arb, recognition of intoxication simplifies therapy, l,lmvever, it is surprising he.w a d v a n c e d digitalis toxicity m a y become before reeognithm. I-~ven if severe enough to cause death, it is not recognized at autopsy f . r there are no patho~znomonie evidences. In fact, i n a d e q u a t e explanation of death is often an imp o r t a n t point in retrospeeh e diagnosis. ]/gc:oexn'zox oF "I'oxlcrr~" Short of prevention of toxicity, recognition of its presence is the most important factor for early applicaticm of active, therapy. In 1S75 V~'illmring. t in his primary, report on di~italis,~. ~ave a lucid description of the evidences of "' it~" w h e n he said t h a t "foxglove when .given in very large ,"I N ( 1 quickly. toxin • r e p e a t e d doses occasions sickness, vomiting, p~rKmg, giddiness, ccmfused vision. objects a p p e a r i n g green or yellow, increased secretion ,ff urine with fre¢luent motions to p a r t with it and sometimes inability to retain it; slow pulse even as slow as 35 in a minute, e~ld sweats, ecmvulsions, syncope azM death?" IAttle m o r e was a d d e d to fl~is description until the cardiac ~rre~ulantms "e ecmlDanving digitalis intoxication V~•~ r e. shown b.y e l e. e t m c. a r d m ~ r a p h v to run . the ~amut of all the usual t? pc.. F o r m a n y years ~he ingestion ~f ~ r ~ n p,Ils or "'~reen drops" w h e n carried to excess was the chief or (mlv factor in pro,I ~ V' duetion of toxicity. TAttle was done for the patient except ~ t h d r , , ~ al of the' dru~, prescription of rest and administrati(m of relatively inefficient diuretics. But today the t r e a t m e n t of digitalis toxicity is not simply the pr~hhm~ of repeatin~ *'~,'~thermgs description of the .~vmploms of overdosa~e, reec~gmtm. ,t ~,, of their assoeiatim~ with intake of digitalis a n d ,,~thdra', ,d of the ¢Iru~ until the s y m p t o m s clear - p . I n d e e d this seq~mnce is still most imp~rtant tr~ reeng* nize ~md correct. But the pr¢>bh,ms of digitalis poisoninR h a v e bee~m~e mr~re ,'~d)9

31(I

w.a.

so~)~::M..~x

c o m p l e x . I n t o x i c a t i o n has b e e n on t h e a s c e n d t m c v d u e ct~iefly to n e w e r p r e p a r a t i o n s a n d h o w tile), a r c used,o a n d to tim gre:~ter COml~h-xities.. of p a t i e n t ' s status r e s u l t i n g f r o m n e w e r f o r m s (~f t h e r a p y . Pt~rified p r e p a r a t i o n s h a v e m i n o r local g a s t r o i n t e s t i r m l i r r i t a t i n g p r o p e r t i e s , mad e t h e r f o r m s of t r e a t m e n t , suc|~ as salt dei)leti~m p r c c e ( l u r e s , o f t e n s i m i l a r l y l)r(Mu(.e a n o r e x i a a n d o t h e r m i n o r g a s t r o i n l e s t i l m l s y m p t o m s . C a r d i a c i r r e g u l a r i t i e s m a y b e t h e first r e c o g n i z e ( I e v i d e n c e s o f d i g i t a l i s e.xcess a n d o f t e n c~mm a n d go. T h e p a t i e n t m a y n o t b e e x a m i n e d w h e n p r e m a t ~ r e l~eats er r u n s ~t" t a c h v c a r d i a are l~resent. . A f t e r b a s i c d i g i t a l i z a t i o n w i t h p~rit3ed p r e p a r a t i o n s , suc}J as digitoxil~, t h e p a t i e n t m a y b e p l a c e d o n s o - c a l l e d m a i n t e m l . c e doses a n d ol s c l x e d c a r e f u l l y for s e v e r a l w e e k s w i t h e v i d e n c e t h a t h e a p p e a r s r e g ~ d a l e d in his d i g i t a l i z a t i o n on at s t a b l e p r o g r a m . S o m e s~mh m a i n t e n a n c e doses, for exam., l)lt at 0.2 rag. l e v e l . m a y o v e r these s a m e w e e k s ! ) r o d u c e a c e : m l u l a t i c n w i t h Iitlle or no g a s t r o intextinal s y m p t o m s , a n d p r e c i p i t a t e i n t o x i c a t i o n w i t h s e v e r e c a r d i a c i r r e g u l a r tiles e n d a n g e r i n g life. IAkewise, in s e v e r e h e a r t f a i l u r e , t h e p r e m n t m ' e b e a t s , electrocardiographic changes and subjective symptoms tony be either a part (ff t h e d i s e a s e p i e t m ' e i tsclf -, or p a r t of digit~dis i n t o x i c a t i o n . T h e a m o u n t of d i g i t a l i s t h e patten! has t a k e n m a y b(: dil[ric~dt to (_,stablish, for h e m a y h a v e t a k e n it irreg~llarly. An e h ~ e t r o c a r d i o g r a m m a y , as s t a t e d a b o v e , s h o w S T a n d T e l m n g e s p r o d u c e d e i t h e r b y d i s e a s e or b y d i g i t a l i s . If p r o d u c e d b y t h e l a t t e r , it u, il| no! n e c e s s a r i l y i n d i c ; i r e i n t o x i c a t i o n . I n d e e d , t h e eleetroear
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f o r e m o s t i m p o r t a n t in diagnc, sis. S o m e of tlwsc, t~r e x a m p l e g r e e n or vPlloxv v i s i o n , a r e n o t u n c o v e r e d n n l e s s t h e pllvsicim~ ]w~:l}es to.r t h e m . |}rotilit/t, tlt i~ " ( "" ~T N ¢ " ~ ' { ' r i l X " IX[ c { } r l e v i d e n c e o f d i g i t a l i s t o x i c i t y in r e c e n t ,,'cars is a n m l ~ "" a ,N :m.., g e s t ] c f a i l u r e w h e n t l m p a t i e n t is on adc{luat,_- o r t'airlv, l a r g e do~cs a n d Ilu' c l i n i c a l p i c t u r e w o r s e ~ s w i t h o u t a p p a r e n t caust,.:: l . : n e x p l a i m ' d c c r c l n ' a l .,..vmptOltlS. ~ dlZZlll{s~, SVllcope. e v i d e n c e s of t o x i c p x - , ' c | ~ c . x c s , parastho.,ias ar~mnd

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d i g i t a l i s , s u c h as i n c r e a s i n g v e n t r i c t l l a r rat¢-s w i t l u m t .~]tcration ill t h e pact:,m a k e r m e c h a n i s m in a t r i a l fiHrillatim~ m a y d e v c h ~ p a.,, tiu, t'{.suit of t h e d r u g . " " A t r i a l flutter, r a r e as a n e v i d e n c e of tiigitalis l{~xicitx', h a s t}t,t'n r e p o r t e d as res u l t i n g f r o m it in s e v e r e h e a r t faihH'c. ~' Atriad | | u t t e r s h ~ t t d lie ~lt~p{'eled as tlut" to d i g i t a l i s i n t o x i c a t i o n w h e n a s s o c i ; | t o d witl~ y e n | t i t u L a r l W e m a t u r t • beat~ d e s p i t e a r a p i d v e n t r i c u l n r r a t e . j~st as it is c o n s i d e r { i t tn t h d t c r iu w e l l d i g i t a l i z e d p a t i e n t s w i t h condos{iv{, h i ' a r t f : d h m , havi~}~ .s|¢m: ve~tri{.ll|ar rates. S u d d e n t a c h v c a r d i a o r t>radvenrtlia, clmng~'s f r o m rc~10:Iritv tt~ irrc2ul;~rit} ot t h e h e a r t , o{7 t h e rt~x'{'tst""" o e c u r r i n ~ d~riu~, therapy, t}I con,,cstiv,,... }u,art failure, s h o u l d b e s u s p e c t e d as n~a,~ifestations o f d i g i t a l i s toxicity. t l e c o g n i t i o n o f t h e s e fin{lin~s is m a t h - {to~blv i~nl}~n't~n~t b e c l m x c evident:t,.s o f m i n o r t o x i c i t y a r e u.~,{ d as t h e e n d Imint for adt,{ltmte ~li~italizuti~,n. Tinm a r g i n b {,t x,x t*~ n tile m o s t t •if{-.{ot~"ve t h e r a p e u t i c d o s e ;rod t~xic d{~se~ is .small. In g e n e r a l , e v i d e n c e .sh~ xxs t h e t | l e r a p e ~ t i c l e v e l is nl}onl (+0 p e r c e n t ~f tim t< x~c r a n g e an(I t h e m a r g i n l}('comt's s l n a l l e r w i t h l}~}tassiutn {I(,ph'titm. lgach p a t i e n t is ;1 prt}l}lem m i t e hims{,lf in his r e a c t i o n t~; ditlitalis ;~{! m~lst b e "'titrated'" a g a i n s t h i m s e l f . X l i n o r svmpt{m~s a n d siKns arc. t h e r e f o r e , oft/.~ "" r c' tht"tht'r;tl:~ist lie has t~ainptl [in" t h e l}atiettt MI d e l i b e r a t e l y p r o d u c e d to •,tss~l tilt" l>c,n e f l t h e c a n f r o m this p o t e n t a n d iml}c'rl-nt {|rt~1. {;~mstaml ~}l}scr,ealit}n a n d w a t c h l w tilt- phvsiciat~ a n d l>v t h e lmtit'nl a r e lht,ref{n'c: vital It} t h e l}r{"v e n t | o n a n d " r e c o g n i t i o n of d i g i t a l i s t{}xicitv a n d arc. t h e r e f o r e , p r i m a r y to •

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treatment.

T h e s p e e i u l prc~l}lom pt.s{{ ," , l I}V {li~it{}xin atl{t s{}nm~]f flu, t:thPr purif]c,] ~iyct,s i d e s s h e u l d n o t I)0 i n t e r p r e t e d as in{licatintl a ~Iit[er{-~me in I}::si{" :lctioll of this d r u g All d i g i t a l i s p r e p a r a t i c , ns h a v e s i m i l a r acti{,n ;rod all p r o t h ~ c e toxicitv i f g i v e n i n a d e q u a t e d o s e s . Sonlt, pret}aratitms, l,avint~ s o m e d i f f e r e n t p r o p e r t i e s f r o m o t h e r s , p o s e s p e c i a l p r o t } l e m s iB toxicltv. D i g i t o x i n . for exa m p l e , h a s t h e p r o p e r t y of f a s t e n i n g itself o n t o blc, v d l>rt~tcins au{t circulate~; in t h e b l o o d for l o n g p e r i o d s o f t i m e . D i g | t o x i n , a~ut t h e leaf. b o t h h a v i n g a l o n g p e r i o d o f {lissipation. a r e f r e q u e n t c a u s e s o f inloxi{':~tit}n) ~ Thi% Drt}pvrty h':~{ls to d i M e u l t v w h e n overall}sage o{'eurs, ft,r t h e {lr~+~ cam}~}t lie d + ' s t r o v e d ~,r excreter1. In a ; d d i t i o n , t h o s e ehan~zes w h i c h m a y l c ; , I to i n c r e a s P d serr,;ilivit,," o f t h e p a t i e n t to d i g i t a l i s m a y p r e c i p i t a t e intt}xi{:athm with{tar ;~
312

w.a.

sO~)est.,x~

vomiting all affect sodium and potassium balance and create circumstances in which the patient~ reaction to digritalis~ increases. A patient well stabilized on digitalis and getting ahmg well for hmg periods of time may, on his usual satisfactory doses, become intoMeated as the result of such effects. F u n d a mental to lhe therapy of such patients is the preventive approach in choice of digitalis preparations. Patiefits with severe or advanced congestive heart failure, in w h o m electrolyte changes from diet and diuretic t h e r a p y are likely, and those in w h o m sm'ge W is c o n t e m p l a t e d or likely, should be digitalized with rapidly excreted products, such as digoxin or even gitalin, to meet toxicit), by rapid excretion. In this way toxicity is met before it occurs. At times digitalis intoxication m a y develop on smalt ~gses of the drug. a This occurs at t i m e s in individuals previously treated with digitalis and in w h o m digitalis elfect has disappeared even for months before the d r u g is reinstituted. In animals with persistent electrolyte disturbances, this sensitivity to small doses has been ",,,'ell demonstrated, a In patients in w h o m dig*italis, has been disc¢mtinued and in w h o m electrolyte distm'banees have persisted, redigitalizalien must tm carried out with c "a H t I:o n . Small doses of digitalis may cause symptoms at times on an allergic basis. Fortunately this occurrence is unusual. Such allergic manifestations are predominantly m'tiearial and erythemalous in D,pe, but asthma has been reported. Eosinophilia and positive skin tests are unusual. AG*Hv~ T.I l ~ a P g Thus far little has been said in this discussion concerning immediate therapy. Such a program must include ( a ) below and may require one or more of the remainder of the follov,,ing: ( a ) Discontinuance of digitalis intake. ( b ) "~Vilhholding of diuretic measures until toxicity clears up. ( e ) Reslrietion of activity of the patient if necessary. ( d ) Administration of potassium salts. ( e ) Chelalmn of serum calcium if necessary. ( f } U s e of procaine amide. I)1. e~mtmuancc of digitalis intake has already been emphasized. As in all intoxications, elimination of the agent is the prime factor in treatment. Anticipation of this need in certain patients subject to increased sensitivity has been pointed out with the importance of choice of preparation. "O.'itl}holding of diuretics stems from the el|eels on electrolytes, and ,,,,'ill be discussed below Mong with the increased sensitivity to digitalis resulting from these effects. lh.striction of activity needs no comment. P~lassimn. calcium, and procaine ran|de require further discussion. P o / a s . s i u m . One of the most important advances in the t h e r a p y of digitalis toxicity rests in the establishment of the relationships of potassium metabolism and the m a n y factors affecting it eo congestive heart failm-e. T h e potassimn content of failiug heart muscle is reduced. Selective failure of either ventricle is accompanied by r e d u c e d potassium content of that musculature. Congestive heart failure stimulates potassimn loss. Recovery is a{eompanied b y potassimn r e t e n t i o n . . M u c h of the therapeutic p r o g r a m in heart failure also produces

T I l E " r ~ r _ A ' r M E x ' r O F ~ i G I T A L I S TOXICIT'I"

~1~

potassium loss for example, salt restriction, diuretic therapy with anunonium chloride, Diamox, dllorothiazide and mercurials. Anoxia, acidosis, ov~,rwork, nutritional failure, diarrhea, vomiting, all tend to chin natc potassimn. ~lercurial diuretics, and especiall-¢ chlorothiazide and its derivatives particularly sweep out potassium. Intravenous glucose, la with or withonl insulin, affec~ potassium levels and m a y lower the serum potassium, a change sehlom seen in b o d y deple~on otherwise. Potassium levels in the blood usually do not show significant changes with potassium loss and therapeutic administration of potassium, when effective, produces no real change in bhmd h.vcls, Ol:,viously it is the cellular level which is important. T h e effect of potassium ions in m)'ocardial function is an old observation. 14,1~ T h e effects of hbq~okalemia and hypcrka|emia on the electrocardiogram are well l.:nown. One would suspect that a drug such as digitalis having profound myocardial effects might also have some relation, in its action, to potassium. This is true. Digitalis action tends to deplete the myecardinm of potassium. Changes in potassium levels in the myocardimn clearly affect digitalis 16 action. A d d e d potasshun protects against digitalis toxicity. If potas. , r"s and continues, the toxic levels ff~,r slum loss from the mvoeardium occu digitalis are reduced and approach therapeutic levels. I,osscs from diuretic action or reductions from glucose therapy may be su||icient to hring about cNtical levels and produce such toxic effects. Digitalis action, maintained at therapeutic levels, m a y become a toxic action when measures increasing p(~tasslum loss develop. This is the basis for so-called "mercurial redigitalization". It is obvious that a multiplicity of factors affecting potassimn mctabc}lism come into p l a y in heart failure and a total evahmtion of these factors playing on potassium metabolism is important. Added potassium has !ong been known to control irritable phenomena such as premature beats or par¢~xysmal taehvcardia, when or when not due to digitalis effects, and is most impt~rtant in controlling the arrhythmias resulting from digitalis ~ntoxication. "a''7 Potassium administration in digitalis toxicity, may. be accmnl~lished, l}v the intravenous or oral route. Intravenous use is reserved for those circumstances rermiring p r o m p t action, such as that in patients in shock frf~m ventricu|Itr tachveardia, in ventrlenlar prcfibrillary rhythms, or with paroxysmal auricular tach;¢cardia with block, all conditions in wl~ich threat tr, life is iml~ortant. Slow" intravenous drip over a period of one to two hours of 20 to ,I0 m | . :¢t.. ( 1.5 to 3 Gin. ) of the chloride in a liter of 5 per cent glucose is commonly tlsed and m a y be repeated if necessau¢. Electrocardiographic monitoring is important for safety. ~ e drug can be stopped ~qth peakin~ of the T wi~ves. V~q~en a theral~entie effect is obtained, one may. then switch to oral rnedicMion. O r ; d l v a ,~.0 Gin. dose is given l m m e d m t e l if necessary: followed by ~ Gin. dose.~ every four hours. ~ l e drn~ is nsuallv given in chilled fruit iuice to minhnize nm,s~,a and gastric irritation. Epiga.£tric distress, loose stools, abdominal distention and metallic taste often occur. In ~eidosis the citrate or acetate may be used. Tablets a ~ n o t recommended for Hmv may not dissolve in the gastrointestinal tract. Care in administration of potassium is necessary in severe renal disease to prevent potassi~m intoxication. Procaine ~tmi¢le m a y be s ~ h stituted.

31d

~v. A. SOD<~AN

f'rocailw amide. In s e v e r e intoxication, for e x m n p l e in suicidal a t t e m p t s , in severe t~mgestiw., h e a r t failure, or in r a p i d p a r o x y s m a l a m ' i c u l a r taehyc.ardia, l~oth p o t a s s i u m a n d p r o c a i n e a m i d e m a y l)e coml)ine{t. P o t a s s i u m a l o n e m a y lint b e ctfect, ¢.....P r o c a i n e a m i d c also a l o n e has a p l a c e in the t r e a t m e n t of the o t h e r a r r h y t h m i a s of digilalis intoxication. It is well a b s o r b e d orally w i t h its aetioll r c a e h i n g its height in a b o u t 90 m i n u t e s . Effects m a y be o b t a i n e d in fo~u" to five m i n u t e s by intr;reenous ~se a n d agah~ e l e c t r o c a r d i o g r a p h i c m o n iloriug is in order, in paroxysmal a u r i c u l a r t a e h y c a r d i a w i t h block, p r o c a i n e anahh' llallv he tried if p o t a s s i m n is not st~ecessfid. I n t r a v e n o u s l y , 50 rag. is givt, n evvrv two m i m l t e s unless t h e h h m d p r e s s u r e d r o p s a n d then it is s t r e t c h e d m a to e v e r y five or ten m i n u t c s . If t h e b l o o d p r e s s u r e still falls, flu' d r u g must l)e StOl)pe(t. If the Q R S c o m p l e x b e c o m e s imtlu:ly p r o l o n g e d . the d r u g m u s t also b e s t o p p e d if v a s o p r e s s o r a g e n t s a r e n o t c o r r e c t i v e . O r a l l y 1.0 Gin. is given al t h e s t a r t w i t h 0,5 gl:n. ever), t h r e e to six hours. A g a i n in renal disease the dose m a y h a v e to b e l o w e r e d . T o x i c i t y i n d n d e s flnshing of the face, giddiness, febrile :rod allergic responses, a n d intravenc, uslv, h y p o tension.

Cetlcittm. Clmlattitm of e a l c i m n Ires its l-)iaee in the therapy, of digitalis int~xicatitm. Is-l~ Potassitun a m l c a l c i u m ions h a v e o p p o s i n g effects ¢:,n the D o g heart ;uld the ~s~mi c o n c e p t is that c a l c i u m ions p o t e n t i a t e digitalis action. Digitalis effects b e c o m e a u g m e n t e d w i t h excessive c a l c i u m a n d a r e r e d u c e d in the al~s¢,nce of c a l c i u m . D e a l h may. ocel" ir in d i g i t a t i z e d p a t i e n t s r e c e i v i n g zl,: " p r o b l e m s of t h e e x a c t relationstfips of a s y n e r ral~i{l c a l c i u m iniections. "~t *4ism are uot clear. / | o w ( , v e r , the l o w e r i n g of c a l c i u m icm le~.~ds in t h e b l o o d b*'IDs digitalis intoxication a d d m a y also stop arrhvthmias, not d u e to diKitalis. Stulium x,ersenate ( I5 FDe ) in 6 ~ rag. closes i n t r a v e n o u s l y , in 250 cc. o f 5 p e r t e n t glucose, has b e e n ~seful in s e v e r e i)oisonin~ a n d has b e e n s u c c e s s f u l a f t e r p o t a s s i u m in~eetions h a v e not Kivcn relief. It m a y b e r e p e a t e d if neeesNlagm,silm~ salts, i n t r a v c n o ~ s l v or i u t r a m u s c u l a r l y , h a v e also b e e n ~sed to relic're digitalis intoxication. Aeticm in (h~ses o f 20 ce. o f t h e _°0 p e r ce~t s~h~lima is of short d u r a t i o n . SU,~INIARY

1. T h e a s e e u d e n e v of digitalis intoxication in r e c e n t years, d u e e s p e c i a l l y to tile use of purified glycosides, m o r e effective diur(-tic p r o c e d u r e s , a n d tluid a n d e l e c t r o l y t e m a n i p u l a t i o n s , h a s m a d e t h e p r e v e n t i v e aF~proaeh an .essential part of treatznent in e v e r y p ,-m"t"n t r e c e i v i n g t h e d r u g . This a p p r o a c h must i n c l u d e ( a ) the d m i e e of p r o m p t l y e x c r e t e d p r e p a r a t i o n s in p a t i e n t s in w h o m surgical or e l e c t r o l y t e m a n i p u h d i o n s s e e m likely: ( h a use ~)f m i n i m a l cI/t,c/ive doses: ( c ) regular o|)serx'ation of t h e l)atiem: (d) r e c o g n i t i o n b y the patient ;as well as by. t h e p h y s i c i a n of t h e e v i d e n c e s of toxicity, a n d ( e ) cart. in the use of p a r e n t e r a l p r e p a r a t i o n s . 2. l/ecognition of digitalis intoxication is f m u t a m e n t a l to active t h e r a p y . T h e •mirth,Iv of it,; d e v e l o p m e n t , e i t h e r t h r o u g h o v e r d o s a g e , or t h r o u g h changes in ch,ct~ol,cte b a l a n c e of t h e p a t i e n t , m u s t b e e o n s t , m t l v k e p t in m i n d . "I,ess cmmmm'" m a n i f e s t a t i o n s m u s t b e s o u g h t out. T h e p a t i e n t m u s t b e a w a r e of

Till+; TltEATNII,~NT {}1: I}I{;I'I'AI+IN T{}XI{;I+I"t"

~]|8

such symptoms. A digitalis tolerance test may be necessary, for (hlh ; : .... ++tm +'a t u:'}n o f t h P {+ |{,eta {}[ {lisease and •Dro~ressivc e|l+ects {ltm to digitalis+ +'I ' + ,'-; v 3. Active t h e r a p y must mctu( + I.c ( a ) dis{~mtimmne{, of the {h+.g and may rP+ quire. {Iepending Ul}{}n circumstance:< ( b ) withhokting of diurtqic measures until toxicity, clears up, ( c ) restriction +ff act|', it+v of thP Flat+t+ '-~+t if necessary+ ( d ) administration of potassium salts+ (e} {+heh|tilm {ff serum calci~m~ if ne{vessary, and ( f ) ~se of prrmaine am|de+ REFERENCES I. \Vithcring, \ V . An Accmmt {d the Fox+ gh}vc. (2trdiac Classics, St. lamis. Mo+. C. V. Mosl}y Co.. 19|I+ 2, l+own, B . Marc~+s, tQ and Levim+, S. A+: I)igilalis and atrial h u h y c a r d i a with bh}ck: A year's experience, New England J,Med. 260:301, 1959. 3. Lown, B+ and lmvi'de, S. A+; {:urrent Concepts in Digitalis "l+hera+~)+ BostoIt. £\Iits,~;. I+ittle Brm~n & Co+, 1954+ 4. So{leman, "W+ A+: Refr:;cl~ny ih'arl Failure+ C;tlifornia Nh+d+ 81:I97. I95-I+ 5+ Shrager, XI+ ~+V+: I)igitalis int+}~i,++ation; it revi+m+ and report of forty case; with +e:nphasis +m etiologq¢. Ar{+h+Int+ XIe{l+ /00:881, I957. 6+ Church+ G+ and Marriott, I1+ J+ L.; I)iv+ ;tabs {h~+liri+m]+ Circulation _( :~ }:a-lh, " { 195.% 7+ Knowlvs, lk IL: Acut{ + m:+ssiv( diyitali> intoxi+ +~ti{m+ Rhode lshmd M+,d+J+ 42: 592, 1,q59. & Bac:mcr+ Nl+: Oc{l~rrenvc of :t rapid yen+ tricu|ar rate during atrial llbrillatiol~ a'~ a t}an~{loxical wa~]ifestiRion of {ligihdis ml+}xication+ Am.lh'art +I+ 56d~85, 1958. 9. Coffman, J+ D+ and Whipple, G. IL: Atrial lhttt, r as a m+mifestatthm oI digitalis toxicity. Circ.lation /9:I88, 1959. Ilk Ararat, is. C+ m d Michaehdes+ G+: Paroxysnml atrial flutter and right Iron+ dle branch block following m g m d ~ therapy. Am+l+ Cardiot. 4:lfil, I959. I I. vonCapeller+ I),. Copcland+ G+ I). amI Stern, q2 ~N+: Digitalis intoxication: A clinical report of 148 Ca+e~+ A+m+lnt+ Xled. 50:869, 1959+

12+ Ska~gN+ |L tI,: ,Mh,r~ir P+wthm t~ dig+ ilali~; {:a~e rPlmrh +!+ev~x S|+m, .l,Med+ 55:.%1, 195!}+ 13+ P:+~:L I;'L Precip;tali,'m of venlrirular ard~ylhmias due to di~itaIis by Padre+ hydrah, admini~trali~m+ Am.J.Med+ 1.9: IbD, I,q55+ 14. Ringer. S. ,rod M,m+cll, ~V+ {Smcer+dng lhe r|h'cl~ on f r o ~ of arresl ~ff ttu' circulalion, aiul an cxplamdiou {ff the act;tin ~f Imtas|~ ~ l l x on flu' aBimal lmdy. J.Pl~ysi++l, 1:72. 187S+ I5. Marlin, E+ {;+: Th{ inhi|~ilory inthwn¢c ot imta~sim, ch|orkb+ on thr hc+rt, :rod the eilecl of varialim~ ~f Iemper:lIllrt+ iIpOi| this inhibilhm and ~q}on vagu.- inhihilim+, Am+J+Phy~iol+ I I: 37O, I .q0+L t(~+ FrhxlmatI, M+ aud lime, Jr,, lhme: Obscrvation~ ccmcPrnh,g tht, mflnence ~ff tmtas~itmt ulum du+ action of a digitalis glycols;d,+ (lanatB~ide C,}+ Am.J. >.hut.So, 214:633. 1947. 17. Chapmati, T+ tl. and Mclien, tl, S.: In+ trawmous potasxilmt dteral}Y ill vt~lltricuIar tachycardia md |ihrillation with Stokes-Adams s,:izurcs secondary to digitalis intoxication, Grace II+}~pital lhdl. 36:39. 1958. 18. (;ulmcr. R. S. and Kalhn:m, I1+: "Fr~lmerit +ff digihdis t+~xit+i/y by chelati~m +}[ ~ertllIl {-;ilcillltI A,n+J.Mcd+Sc+23.1: 136, t957. 19. l}e~+stein+ M. S.. Ne~{hi~+ M. mM Col+ tini. IC: Trl-atl+l~mI of ;ICIltt~ I|la~iV~ digitalis poi~ming bY ad+mni~tratian {if a d m l a t i u g ag{nt+ New England J+Mvd. 2~'ildJ61, 1959,