Use of edrophonium chloride (Tensilon) to detect early digitalis toxicity

Report on Therapy Use of Edrophonium

Chloride

(Tensilon)

to

Detect Early Digitalis Toxicity* BERTRAM PITT,

M.D.?

Boston,

and GEORGE s. KURLAND, M.D. Massachusetts

D

and LevineY have sought to utilize the increased sensitivity of the carotid sinus reflex in digitalized patients; a recent report’” has advocated the use of neostigmine to assess the degree of digitalization in patients with atria1 fibrillation. This report presents our experience with the llse of edrophonium chloride (Tensilon@), a shortacting acetylcholine-esterase inhibitor, to detect early digitalis toxicity.

IGITALIS intoxication is an increasingly frequent clinical problem. Many reviews that have described the signs, symptoms and therapy of this disorder have stressed the narrow range between full therapeutic dose and toxicity.‘-” At full digitalization, 60 per cent of the toxic dose has been administered. At the onset of toxicity, the patient has received 40 per cent In patients with congestive of the lethal dose.2 heart failure, the therapeutic index is even less.” When a careful history of digitalis dosage is combined with the symptoms, signs and electrocardiographic evidence, the diagnosis of digitalis intoxication is established in most instances. If proper therapy is in doubt, digitalis can often be withheld. There are instances in which circumstances suggest digitalis excess, but the history of digitalis administration is inadequate and withholding of digitalis may be harmful. For example, ectopic ventricular beats, which are frequently associated with digitalis intoxication, may also be found in congestive heart failure and in this instance may decrease after Atria1 fibrillation may itself be digitalization.6 When a manifestation of digitalis intoxication.’ this occurs, the ventricular rate, which is usually a good indicator of the degree of digitalization, may be misleading since it may increase rather than decrease as a result of digitalis toxicity.8 Numerous efforts have been made to solve the dilemma of digitalis administration under these circumstances. These have included the use of calcium, ethylene diamine tetracetic acid and acetylstrophantidin; (EDTA), potassium, none has been generally accepted.2-4 Lown

METHODS Thirty patients at various stages of digitalization were studied. Five or 10 mg. of edrophonium chloride were administered through the tubing of an intraThe venous infusion of 5yo dextrose and water. electrocardiogram was continuously monitored from 5 minutes before until 15 minutes after the injection of edrophonium. Atropine and emergency equipment for cardiac resuscitation were constantly available. In some patients, the carotid sinus was stimulated prior to the administration of edrophonium. Decisions concerning clinical management were made without knowledge of the results of the edrophonium test.

RESULTS The effects of edrophonium were usually evident within one to three minutes after its intravenous administration and subsided within 10 to 15 minutes. Edrophonium was administered to 12 patients prior to digitalization (Table I). Nine had atria1 fibrillation or flutter; two, sinus rhythm; and one, paroxysmal atria1 tachycardia with block. In 8 of these 12 cases, there was no significant change in ventricular rate (Fig. 1,

* From study was

the Departments of Medicine, Beth Israel Hospital and Harvard Medical School, Boston, Mass. aided in part by a grant from the U. S. Public Health Service, Program Project Grant HE-06316. t Presently National Heart Institute Special Fellow, Johns Hopkins University Medical School, Baltimore.

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TABLE I Results of Administration

&SC2 NO.

of Edrophonium

Prior to or During Digitalization

Age & Sex

Digitalis

1

89F

NOW

3

78F

None 0.5 mg.

7

72F

None

9

72F

None

11

78F

12

46F

15

51F

1.25

mg.

digoxin

1.25 mg.

1.2

mg.

digoxin

digoxin

digitoxin

Effect of Carotid Sinus Pressure

_-----Rhythm-------.

Dosage

A.F., V.R. 140-150. Occasional PVB’s with fixed coupling V.R. 90-120

t.v.

A.F., V.R.

I.V.

I.V.

orally

V.R. 130-150. 90-130

Frequent coupling

A.FI., V.R. 60-90. PVB’s with fixed V.R. 70

Frequent coupling

PAT with PVB’S

Non.?

block,

V.R.

120.

A.F., V.R. 150-160. PVB’s with fixed

17

68F

NOllC

A.F.,

58M

None

A.F., V.R. 140-150. PBV’s with fixed V.R. 90

22

68F

NOW

Sinus rhythm, V.R. sional PVB’s with pling

90. Occafixed cou-

24

71F

NOIX

A.F., V.R. 100-110. PVB’s with fixed

Occasional coupling

28

25M

NOW

A.FI., V.R.

0.9

A.F. = atria1 fibrillation; rate; PAT = paroxysmal

mg.

digitoxin

A.FI.

orally

= atria1

flutter;

C.H.F.

V.R.

Occasional coupling

21

V.R. 180

120-150.

180.

Unchanged

V.R.

slowed

to 80

80

Unchanged

100 Unchanged

None N0o.Z

Unchanged

Unchanged

40

Unchanged

Unchanged

Unchanged

40

Unchanged

90

2 single PVB’s

Unchanged

Unchanged

Unchanged

Unchanged

V.R.

slowed

to 90

unchanged

= congestive

V.R.unchanged

80

None

V.R.

slowed

to 100

110

Unchanged

V.R.

slowed

to 40

60

Unchanged

Unchanged

Unchanged

Unchanged

Unchanged

Unchanged 90

None NOTIe

No PVB’s Frequent coupling

No

V.R. V.R.

PVB’s

heart

failure;

PVB’s

unchanged unchanged

= premature

ventricular

beats;

V.R.

=

ventricular

atrial tachycardia.

W; in the remaining 4, there was a decrease Eight of the in rate of 30 beats/min. or more. 12 patients demonstrated premature ventricular beats with fixed coupling prior to the infusion of edrophonium. None showed an increased incidence of coupling or the appearance of other foci of ectopic ventricular activity after edro-

. FIG. 1. minutes 1.2 mg. prior to

to 90

Sinus rhythm, V.R. 80. Occasional PVB’s with fixed coupling NOX

Unchanged

s

slowed

V.R.

No

of Edroohonium PVB’S

V.R.

No PVB’s

A.F., V.R. 130-140. PVB’s with fixed V.R.90-100

Effect V.R.

phonium (Fig. 1, 2). Therapeutic doses of digitalis were subsequently administered to 6 of the 12 patients who were again tested with edrophonium. Five of the 6 then showed a greater decrease in ventricular rate than had been noted with edrophonium prior todigitalization (Fig. 1,2B).

_ ,: _ _.. _ _

. ii

Case 7. Effect ofedrophonium in a 72 year old woman prior to and during digitalization. lA, control. lB, two after edrophonium. Note the absence of ectopic ventricular activity. 2A, twelve hours after digitoxin, 2B, one minute after edrophonium there is a greater slowing of the ventricular rate than orally; control. digitalization. THE

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Edrophonium

FIG. after

2. Case 12. edrophonium.

Chloride

in IXgitalis

of Administration

II

of Edrophonium

in Patients

with

*w & Sex

2

54F

2

Digitalis

Dosage

Accidental ingestion of large amount digitoxin

Chronic

0.1 mg. digitoxin 4 times daily

A.F., V.R. 70-90. Occasional with variable coupling

orally

V.R.

Paroxysmal A.F., casional PVB’s pling

Digitalis

Intoxication

_-Effect V.R.

Rhythm

A.F.,

minute

coupling developed after edrophonimn but were not present in the control electrocardiogram. Second degree A-1’ block developed in 1 patient after edrophonilun. Xine patients were studied in whom the question of digitalis intoxication was raised (Table III). However, the history and subsequent hospital course led the clinician to discard the diagnosis and to continue administration of digitalis. Eight had atria1 fibrillation and 1, sinus rhythm. Seven of the 9 showed marked slowing of ventricular rate after edrophonium. Five of the 9 had occasional coupled premature ventriclilar beats

TABLE Results

NO.

SSO

Effect of edrophonium in a 46 year old undigitaliztd woman with hi~gpminy. A, control. H, one Note the lack of significant change in ventricular rat? or ectopic ventricular activity.

.Vine patients whose clinical history and hospital course Juggested digitalis intoxication were studied (Table II). Seven had atria1 fibrillation and 2, sinus rhythm. Seven of the 9 showed slowing of the ventricular rate of more than 30 beats/ min. after edrophonium; 2 with occasional ectopic ventricular beats with fixed coupling showed progression to bigeminy; 4 with occasional ectopic ventricular beats with variable coupling, had a markedly increased incidence of multifocal ectopic ventricular beats (Fig. 3, 4). In one instance (Fig. 5) fixed ventricular coupling, and in another (Fig. 6), variable ventricular

case

Toxicity

70-90.

No PVB’s

PVB’s

V.R. 110-120. Ocwith variable cow

of EdrophoniumP\‘B’S

-

70

Increase

with Irigcminy

50

Incrresr

with bigeminy

Unchanged

Ventricular

fibrillation

5

73F

Large amount toxin orally

10

54F

0.1 mg. digitoxin orally 4 times daily, then 0.2 mg. for 2 days

Sinus rhythm, V.R. 80. Frequent PVB’s with fixed coupling

llnchanged

Increase

No digitalis No digitalis

V.R. 70. V.R. 70. pling

Unchanged Unchanged

Short runs of trigeminy Unchanged

IO

of digi-

2 days 7 days

No PVB’s Rare PVB’s

with fixed cou-

with trigrminy

14

68F

0.1 mg. digitoxin orally 4 times daily No digitalis 7 days

Chronic A.F., V.R. 120-130. Occssional PVB’s with fixed coupling V.R. 90-120. No PVB’s

50-60

Increasr

70-90

None

19

90M

0.15 gm. digitalis leaf orally 4 times daily

Chronic

No PVB’s

60-70

Multifocal variable

PVB’s with coupling

20

64F

0.1 mg. digitoxin orally 4 times daily No digitalis 4 days

Chronic A.F., V.R. 70-90. Occasional PVB’s with variable coupling V.R. 90-l 10. No PVB’s

40-50

Multifocal variable Incre;,re

PVB’s with coupling

0.1 mg. digitoxin orally 4 times daily 1 mg. digoxin orally & 0.5 mg. 1.X’. after having been off digitoxin 14 days

Sinus rhythm, V.R. 1 dropped beat Chronic k.F., V.R. sional PVB’s with and runs of nodal

2

0.1 mg. digitoxin orally 4 times daily Off digit&n 3 days Redigitalized with digitoxin 1.2 mg. orally

Chronic A.F., V.R. 120-130. Multifocal PVB’s with variable coupling V.R. 90-l 10. Occasional PVB’s V.R. 80-100; no PVB’s

25

78F

26

71F

30

70F

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A.F.,

V.R.

90-110.

110.

No PVB’s.

90-110. Occnvariable couDline tachycardia . _

70

: 1A-V

block

with higcminy

None

50

Increase with variable coupling

60

Increase with triable coupling Occasional PVB None

50-60 50

Pitt

560

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Kurland

1 B, one and ;I ITffm OJ’ rdrofihomrm in n 0 I YPU old womm, with d/.qi/alii tn/o.\irn~/on. I.\, control. FIG. 3. Case 20. lC, four minutes after edrophonium. half minutes after edrophonium there is marked slowing of thr xcntricular rate. 2, patient rerci\-ed 0.2 mg. digitoxin orally the same Note the appearance of multifocal ectopic vrntricular beats. The electrocardiogram was taken the following day. Note the increase in ventricular day as the edrophonium test. ;\fter withdrawal of digitalis, ventricular coupling disappeared. coupling as compared to the control tracing (l,\).

myocardial infarction and digitalis intoxication had an urge to defecate eight minutes after reWhile she was straining ceiving edrophonium. on a bedpan ventricular tachycardia developed which failed to respond to therapy, including closed chest cardiac massage, external countershock and procaine amide; she died one hour The combinaafter receiving edrophonium. tion of edrophonium, straining on the bedpan,

In contrast to the findings in prior to testing. patients with digitalis intoxication, there was no increase in the incidence of ventricular coupling or of ventricular ectopic activity after edrophonium. Tile side eflects following tile administration oj edrophonium consisted of abdominal cramps in 2 nausea and vomiting in 1, and patients, diaphoresis in 2. One patient with a recent

TABLE m Kesults of Administration

of Edrophonium

in Patients with Unconfirmed

Ai?= Case NO.

& Sex

Digitalis

Dosage

Effect of Carotid Sinus Pressure

Rhythm

4

76F

0.2 mg. digitoxin orally every other day

Paroxysmal A.F., No PVB’s

6

71F

0.1 mg. digitoxin 4 times daily

Paroxysmal A.F., V.R. 110-140. Occasional PVB’s with fixed coupling

V.R.

slowed

8

55F

0.1 mg. digitoxin orally 4 times daily and 0.2 on day of admission

Chronic A-F., Occasional coupling

160-180. fixed

V.R.

13

77M

0.1 mg. digitoxin 4 times daily

orally

Chronic A.F., V.R. 80-100. Occasional PVB’s with fixed coupling

V.R.

18

87F

0.1 mg. digitoxin 4 times daily

orally

Chronic A.F., PVB’s

V.R.

70-80.

18

56F

0.1 mg. digit&n 4 times daily

orally

Chronic A.F., No PVB’s

V.R.

120-130.

V.R.

slowed

23

73F

0.1 mg. digitalis leaf orally 4 times daily

Chronic A.F., No PVB’s

V.R.

100-120.

V.R.

27

57M

0.1 mg. digit&n 4 times daily

orally

Paroxysmal A.F., V.R. 110-120. Occasional PVB’s with fixed coupling

29

77F

0.25 mg. digoxin 4 times daily

orally

Sinus rhythm, V.R. 100. Frequent PVB’s with fixed cow pling

orally

V.R.

Digitalis

V.R.

120-130.

PVB’s with

Intoxication

--Effect V.R.

of Edrophonium, PVB’s

80 to 90

35

Unchanged

unchanged

I10

linchangrd

slowed

60

Unchanged

50

NO”C

to 110

80

Single

PVB

slowed

to 30

90

Single

PVB

V.R.

slowed

to 100

80

Single PVB from 1 second focus

V.R.

unchanged

Unchanged

Unchanged

to 60

No

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-B A

~,~s-.___._

. . .

_

._i. I.

I

“.__

;

ICffecl of rdrophonium in (I 70 yeor old womm aith cliyitoli* intoxicdwri. 1 :\, control. lR, one minute after cdrophonium. Note the slowing of the ventricular rate and the increase in multifocal ectopic v=ntriculx beats. IC, four minutes after edrophonium. ‘I’hcrc is an increase in tixcd ventricular coupling. ID, thirteen minutes after cdrophonium the ectopic activity is diminished. 2:1, three days after withdrawal of digitalis: control. 2B, two minutes after edrophonium. There is still a marked slowing of the vcntricular rate but no significant increase in cctopic ventricular beats. FIG. 4.

Case 30.

FIG. 5. Case 2. E.ect of ~drophonium in a 54 ymr old woman with dz,qitnlu intoxicrctmn. 1.2, control. 1 B, one minute after edrophonium there is a marked slowing of the ventricular rate. 1C. one and a half minutes after rdrophonium. Note the appearance of fixed ventricular coupling.

FIG. 6. Case 10. Effectof P&Ophonium in a 64 year old female with 1 A, control. digitalis intoxicatmn. lB, seven minutes after edrophonium there is an increased incidence of fixed coupling without a change in the basic sinoatriai rate. ZA, two days after the withdrawal of digitalis; control. 2B, eight minutes after edrophonium an increase in fixed ventricular coupling can still be demonstrated.

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digitalis intoxication and myocardial infarction, all factors which are known to increase the sensitivity of the myocardium to vagal stimuli, were believed responsible for the arrhythmia. DISCUSSION The effects of edrophonium on cardiac rhythm at various stages of digitalization are similar to those reported following carotid sinus The ventricular rate of patients stimulation.g with atria1 fibrillation not treated with digitalis occasionally showed slowing after edrophonium; those at optimal digitalization generally showed In patients to whom a more marked slowing. repeated test doses of edrophonium were administered during digitalization, an effect on ventricular rate was frequently not evident until nearly the full dose of digitalis had been administered. Although slowing of the ventricular rate by 30 beats or more after edrophonium was most frequent in the patients almost fully digitalized, this response (which is the basis of the neostigmine test to estimate the degree of digitalization in patients with atria1 fibrillation”‘) is too variable to be used alone as a guide to digitalization. Occasionally ectopic ventricular beats with fixed coupling complicated atria1 fibrillation to digitalization. In these instances, prior edrophonium had little effect on ventricular rate and did not lead to a significant increase in In contrast, in the presence of coupling. digitalis toxicity edrophonium almost always slowed the ventricular rate and consistently increased the incidence of coupled beats. In cases of digitalis intoxication with variable coupling, edrophonium slowed the ventricular rate and led to the appearance of multifocal ventricular beats or runs of ventricular tachyIn 1 patient with congestive heart cardia. failure, atria1 fibrillation, and occasional ectopic ventricular beats with variable coupling, administration of 5 mg. of edrophonium led to inA decision creased ventricular ectopic activity. was made on clinical grounds that the patient was not suffering from digitalis intoxication. An extra 0.2 mg. of digitoxin was prescribed and was followed by prolonged ventricular ectopic activity (Fig. 3). In those instances of atria1 fibrillation with coupled ventricular beats, when edrophonium did not increase the incidence of coupling, further increments of digitalis slowed the ventricular rate and in some instances diminished the incidence of coupling. Although our experience with edrophonium

in patients with normal sinus rhythm is limited, the results appear similar to those in patients with atria1 fibrillation. The vast clinical experience with carotid sinus stimulation would seem to recommend it as the vagomimetic procedure of choice. The variability of its effects on ventricular ectopic activity, I1 however, suggested a search for a more reliable method. The effect of carotid sinus stimulation depends in part on the technic of the operator and on the sensitivity of the carotid sinus, which varies greatly; it may be exaggerated by coronary artery disease and advancing age.‘” *13 Edrophonium appears to be a more desirable cholinesterase inhibitor than neostigmine for detecting digitalis toxicity because its duration of action is shorter. It has no significant effects on blood pressure or pulse rate of normal individuals, although it may induce bradycardia in anesthetized patients.14 No fatalities have previously been reported with its use. The reported side effects are transient and consist of blurred vision, lacrimation, muscular fasciculations, occasional nausea and vague abdominal discon~fort.‘“-‘7 It has been used extensively for the diagnosis of myasthenia gravis and as a curare antagonist in anesthetized patients. The suggested contraindications include bronchial asthma, peptic ulcer and acute myocardial infarction. Mechanism of Action of Edrophonium in Digitalis Toxicity: The multifocal ventricular ectopic beats and ventricular tachycardia that we have observed after edrophonium in patients with digitalis intoxication, atria1 fibrillation and ventricular ectopic activity with variable coupling can be best explained by the action of the vagus conduction. When the on atrioventricular ventricular rate is sufhciently slowed due to enhanced atrioventricular block, there is an opportunity for ectopic ventricular centers to be With increasing increments of unmasked. digitalis the automaticity of the Purkinje system is at first depressed; as digita is is continued, this depression of automaticity is replaced by a progressive stimulation that may produce a continuously and rapidly firing ventricular focus.‘x Early in the course of digitalis intoxication such a focus may be latent due to suppression by a more rapidly firing supraventricular focus. It is at this point that vagal stimulation is of most value in uncovering digitalis intoxication by slowing the supraventricular rate. Acetylstrophanthidin,ig when used under similar cirTHE

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Edrophonium

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cultIsta1ice to rc\.eal digitalis excess, carries a greater risk since it may aggravate the toxicit). and illcrease the automaticity of the specialized conducting systenl. As a result, a latent, slo~vly firing. single ventricular focus may be changed into ml~ltiple, more rapidly firing centers that can gain control of ventricular activity. The increase in automaticity with excess digitalis is not invariable, however, and on occasion, slowing of the ventricular rate by vagal stimulation may result in ventricular arrest.‘” The appearance of fixed coupling during vagal stimulation in patients with digitalis intoxication has been explained on the basis of the re-entry phenomenon.*O Although re-entry could account for the increase in ventricular coupling in some of our patients, it is difficult to see how vagal stimulation that fails to slow the ventricular rate could increase coupling solely on the basis of a re-entry phenomenon (Fig. 5). for fixed ventricular Another explanation coupling states that the extra beat originates in a center where the cells under certain conditions depolarize twice for each supraventricular beat (re-excitation), resulting in an extrasystole with The extrasystole is entirely fixed coupling.” dependent on the initiating supraventricular beat, and there is no increase in ventricular autornaticity.” Electrical stimulation of the vagus nerve in digitalis-intoxicated dogs with fixed coupling results in a slowing of the ventricular rate and a decrease in the incidence of in patients with In contrast, corlpling.‘8 the administration of intoxication, digitalis edrophonium increases the incidence of coupling despite a reduction in ventricular rate (Fig. 5). If the theory of re-excitation is valid, the vagal action of edrophonium, resulting in a slowing of the ventricular rate, is unlikely to account for an increase in coupling since there is no convincing evidence of vagal innervation of the specialized conducting system of the ventricle or of the ventricular muscle itself. Furthermore, vagal stilnulation during runs of ventricular tachycardia is without effect.18 Fixed ventricular coupling may also be due to a parasystolic focus.?l A coupled beat, due to this mechanism, occurs when the parasystolic focus, which is subthreshold at other times, fires during the supernormal period. The vagal action of edrophonium would be unlikely to catise the increase in coupling seen in our patients after administration of edrophonium. A sympathomimetic action of edrophoniurn and similarly of prolonged carotid sinus stimulaVOI.UMP.

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Toxicit),

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tion could account for the incrcasc in coIlplinK despite a decreased or unchanged \Tentricrrla r rate. The accumulation of acetylcholine cl~lc to esterase inhibition or a direct choliner,+c (nicotinic) effect of edrophoniurn collld callsc stirnulation of the postganglionic s>,rnpathetic fibers leading to local release of catccholatllines. This hypothesis gathers some support froitl the finding that edrophonium in atropinized patients causes a rise in blood pressureI and froill animal experirnents showing catecholatuinc release after acetylcholine or nicotine,” -?li Digitalis is known to sensitize the myocardium to the arrhythmic effects of catecholamines, and conversely, beta adrenergic blockade has been used to eliminate ventricular ectopic arrhythmia due to digitalis intoxication.Z7,“8 Ftlrthcrillore, catecholamine depletion in cats eliiilinates ventricular arrhythmias produced by the coinbination of vagal stimulation and small doses of acetylstrophanthidin.P9 A final explanation foi the action of edrophonium must, howe\,er. await a clearer understanding of the inechanism for fixed coupling, documentation of catecholaminc release during cholinesterase inhibition, and further investigation of the action of acetylcholinc on the specialized conducting systcni. Clinical Applications: Since the ventriculat response to carotid sinus stimulation is variable”’ and experience with edrophonium is limited, WC advise caution in the clinical application of an) vagolnimetic method for the diagnosis of digitalis toxicity. \Ye would, however, suggest the following plan as a basis for further evalnation. In patients with a history or electrocardiogram suggestive of digitalis intoxication, digitalis should be withheld. If the patient’s history is inadequate or his hospital course is coinplicated by severe electrolyte disturbances, digitalis Ina! also be withheld when the clinical sitnation permits. Patients with congestive heart failure and supraventricular arrhythmias with rapid ventricular rates in conjunction with ventricular The difficult) extrasystoles present a problem. of evaluating the risk of precipitating ventricltlat arrhythmias on the one hand and the risk of progressive cardiac decompensation from withholding digitalis on the other have given inlpetus Carotid to the use of additional procedures. sinus stimulation should be attelnptecl first hcIn cause of the wide experience with its use. those patients with variable ventricular coupling in whom ventricular ectopic activity increases 01 in whom ventricular arrest occurs after carotid sinus pressure, further digitalis should be with-

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held. When carotid sinus pressure is without effect on ventricular rate or produces only slight slowing without any increase in ectopic ventricular activity, edrophonium may be infused, first in a 5 mg. dose and subsequently in a 10 mg. dose, if initial results are inconclusive. Any increase in the frequency of ventricular coupling or ventricular ectopic activity following edrophonium is evidence for withholding further digitalis. Although no fatalities have been reported with edrophonium when used as a test for myasthenia gravis or as a curare antagonist in anesthetized patients, the one death in our series and the few cases of fatal ventricular arrhythmias occurring during carotid stimulation in digitalized patients2gs30 emphasize the need for caution in the use of such methods. Vagal stimulation in a digitalized patient should not be attempted unless a definite indication exists and then only in the presence of facilities for constant electrocardiographic monitoring and emergency resuscitation. SUMMARY Edrophonium chloride (Tensilon), a shortacting acetylcholinesterase inhibitor, was given to 30 patients at various stages of digitalization. The results are similar to those reported with carotid sinus stimulation. Although slowing of the ventricular rate after edrophonium was most marked in patients close to full digitalization, this response is too variable to be used as a guide to digitalization. Edrophonium increased the incidence of variable and fixed coupled premature ventricular beats in patients with digitalis intoxication but not in other patients. A plan is presented for the diagnosis of digitalis intoxication that involves the use of vagal stimulation by carotid sinus stimulation and administration of edrophonium. ACKNOWLEDGMENT The authors wish to thank Dr. Brian F. Hoffman for his kind assistance in reviewing the manuscript and Dr. Richard Doherty for help in the initial phase of this study.

Kurland

6.

7.

8.

9. 10.

11.

12.

13.

14.

15.

16.

17.

18.

19.

20.

21.

REFERENCES 1. VON CAPELLER, D., COPELAND, G. D. and STERN, T. N. Digitalis toxicity, A clinical report of 148 cases. -Ann. Znt. Med., 50: 869, 1959: 2. LOWN., B., BLACK. H. and MOORE, F. D. Digitalis, electrolytes and the surgical patient. A;n. J: Cardiol., 6: 309, 1960. 3. SOMLYO, A. P. The toxicity of digitalis. Am. J. Cardiol., 5: 523, 1960. 4. LOWN, B. and LEVINE, S. A. Cm-rent Concepts in Digitalis Therapy, pp. 29, 114. Boston, 1954. Little Brown & Co.

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