Complete Atrioventricular Block Treated

with Isoproterenol Hydrochloride*

DOUGLAS CHANDLER, M.D. and MUIR I. CLAPPER, M.D.

Detroit, Michigan

T HE MANAGEMENT of the patient with Adams-

Stokes attacks due to complete heart block

is indeed a challenging problem. The many

medications recommended certainly- indicate

the lack of effectiveness of any one preparation

in the treatment of this often incapacitating

illness. Therapy is usually directed either

toward blocking the vagal cardioinhibitory ac-

tion or by stimulating cardiac acceleration with

sympathomimetic drugs in a manner similar to

sympathetic discharge. The vagus has been

shown to have only a minimal effect on the activity of the ventricles. Therefore, clinical

attempts at amelioration of Adams-Stokes

attacks by vagal inhibition are often not success-

ful. Sympathomimetic drugs accelerate the

idioi-entricular rhythm, but have as their

drawback the fact that they ma)- produce pre-

mature beats or other more serious ventricular

arrhythmias as well as an increase in blood

pressure. A sympathomimetic amine capable of in-

creasing the heart rate without the foregoing untoward effects would certainly he a welcome

addition to the medical treatment of this dis- order. The ideal therapy would be a single

effective oral preparation. Nathanson and

MillcrlP3 introduced the use of isoprotercnol HCl in the treatment of complete heart block. We have repeated their acute studies and, in addition. have utilized the sublingual route for prolonged maintenance therapy in a group of cases with the Adams-Stokes syndromr due to complete heart block.

MATERIAL

Twelve men and one woman with complete

heart block were studied. The age range was from 55 to 76 years. Seven patients had Adams-

Stokes episodes and five required hospitaliza-

tion. The period during which syncopal epi-

sodes occurred before isoproterenol HCl therap)

was started varied from one day to twenty

years. Three patients continued to have asys- tolic convulsions while under therapy with

atropinc, tincture of belladonna, aqueous and oily solutions of epinephrine and ephedrine, alone or in combination.

METHODS

Thirteen patients with complete heart block

were given 15-20 mg of isoproterenol (Isuprel)

HClt sublingually. Serial electrocardiograms

were taken every five minutes for the first hour

and every fifteen minutes thereafter until the

heart rate returned to control levels. Each of

seven patients on separate occasions received

subcutaneously 0.2 mg of isoproterenol HCl and 1.0 mg of epinephrine in order to compare the cardiac-accelerating effect of these two drugs.

Serial electrocardiograms were taken every minute for fifteen minutes and then cvcry fivr to fifteen minutes until control levels were

reached. Seven patients were studied on prolonged suh-

lingual therapy. Doses varied from 10 mg

every two hours to 20 mg every three hours. The medication was taken only during the lvaking hours.

* From the Department of Mcdicinr, Receiving Hospital and Waynr State University College of Mrdicinc. Deioit,

Michigan. t Supplied through the courtesy of the Medical Research Dept., Winthrop Laboratories, New York.

336 TIE AMERICAN JOURNAL OF CARDIOLOCE

Chandler and Clapper

KESI~LTS

Se\,en of the thirteen patients given the sub-

lingual preparation had a significant accele- ration in iclio~-entri~ulirr rate (Tatjle I). X

T:\BI,E I

Average Response of Cardiac Rate to Isoprotercnol and

Epinephrine in Paticants with Completr Atrioventricular

Hock

Isoprotercnol Epirwph-

Sub- Subcu- rine, sub-

~~ brf__ taneous cutayy

Significant 7of13 7 of7 5 of7

rrsponse (no. patients)

Control rat<, 33 33 33

Onset (min 1 21 4.1 25

Peak time (min I 33 8 45

Peak rate 5 1 58 62

Duration (min) 86 72 74

response was considered significant when the

cardiac rate after medication exceeded the

control rate by at least ten beats per minute. In these seven patients the average interval

before this significant increase in rate occurred

was 21 minutes. The average interval before the peak rate was reached was 39 minutes

(range 30~58), and the average rate at this time was .51 beats per minute. The average

duration of action after the time of onset of the response was 86 minutes. The average rise

from control levels to the maximal rate was 18.7 beats per minute (range 12-33).

Five of the six patients who did not respond

to the 15 mg dose also failed to respond to 20 mg. One patient who failed to respond to smaller doses reacted to 2.5 In<: with a slight increase in rate.

All of seven patients given 0.2 mg- isoprotere-

no1 subcutaneously had a significant response. In four of these seven the heart rate had not increased after the sublingual test dose. The average time of onset of this response was 4.1 minutes (range 2-7). The maximal rate was reached at 8 minutes (range 7-20). The aver- age duration of action was 72 minutes (range

MARCH, 1959

28.-144). The a\‘erage peak heart rate was

38 tjcats per ntinute (range 4.5-96‘). The aver-

age increase in rate above the control level was 25 ‘Ieats per minute.

Sc\.en patients received 1 .O mg cpinephrine

subcritancousl~-. Fi\,e had a significant rc-

sponsc. The average time of onset \zas 2.5

minutes (range 15 to 60). The peak rate.

averaging 62 treats per minute, occurred after an a\-erage of 45 minutes (range X--48). ‘I’hc

duratioii -of activit! from the time of onset until control rates were reached a\-eragcd 74 minutes

(range 15-l 35). The average increase in rate

from control levels to the point of maximum

stimulation was 29 beats per minute. 0111~

ox patient (case 4) had a better response to cpi-

nephrine than to subcutaneous isoprotertnol.

.A comparison of the effect of these two drugs on the heart rates of the first six patients in this

series is sholvn in Figure 1.

i--- 70 1~

IO-

Fig. 1. Comparison of average effect in 6 patients given a single subcutaneous dose of isoproterenol (0.2 mg ) and epinephrine (1 .O mg).

PROLOKGED STUDY

Se\.en patients with Adams-Stokes episodes were treated with sublingual isoproterenol HCI for periods from three and one-half days to

nine months. In only one patient (case 3) was it necessary to change to the parenteral form of the drug because of failure of sublingual admin-

istration to prc\‘ent asystolic convulsions. The remainin,g six patients had no further Adams- Stokes episodes while receiving adequate doses of the medication sublingually. In four of these cases the Adams-Stokes attacks reappeared when the medication was discontinued or administered at less frequent intervals. Three

338 Complete AV Block Treated with Isoproterenol

of these patients initially received other medica- tion for periods of from one to five weeks but

continued to have convulsions. During the sub-

sequent sublingual administration of adequate

doses of isoproterenol no such attacks occurred.

CASE HISTORIES

CASE 1. \Y. I;., a 70-year-old Negro male, was ad-

mitted with a pulse rate of lo-12 beats per minute and

was having convulsions in the supine position. Electro-

cardiograms revealed complete atrioventricular

block.6~6~‘5 The response to one 20 mg sublingual dose

of isoproterenol was prompt, with acceleration of the

heart rate to 30-35 beats per minute. Continued sub-

lingual therapy with 20-30 mg at three-hour intervals

maintained a cardiac rate of 30 to 60 beats per minute.

He became more alert and had no further convulsions.

This improvement in heart rate and clinical condition

continued for eight days when a sudden severe upper

gastrointestinal hemorrhage resulted in death.

CASE 2. J. N., a 67-year-old white male, had ex-

perienced infrequent Adams-Stokes episodes for twenty

years. Atropine and ephedrine seemed to control these

attacks until two weeks prior to admission when they

became more frequent, necessitating hospitalization.

The electrocardiogram revealed complete heart block.

During the week of control therapy with atropine and

an oily preparation of epinephrine the patient had no

asystolic convulsions. When these medications were dis-

continued the convulsions recurred. lsoproterenol was

then begun in a dose of 10 mg sublingually every two

hours, and no convulsion occurred for a period of three

and one-half days. The inadvertent omission of this

medication for a 24-hour period was responsible for

another series of asystolic convulsions which were not

abolished by aqueous rpinephrine. The patient died

in one of these episodes.

CASE 3. J. \t’.,,’ a 55-year-old white male, was

admitted in cardiac decompensation with a heart rate of

28 per minute. He had suffered one episode of syncope

two weeks prior to admission. There was no recurrence

prior to entrance or during the initial eleven days of

hospitalization. Electrocardiograms showed complete

atriovcntricular block.

On the twelfth day a series of asystolic convulsions

began which continued over a period of sixteen hours.

These could not be controlled by the routine medications

or by the usual sublingual doses of isoproterenol. An

electrical cardiac stimulator was then used, with im-

mediate restoration of rhythmical cardiac contraction.

An intravenous infusion of 1.0 mg isoprotercnol in 200

ml of 5% glucose in water was then started at a rate of

5 pg per minute. When the stimulator was turned off

20 minutes later the patient’s heart contracted spon-

taneously at a rate of 44 per minute and continued to do

so during the remainder of the isoprotrrenol infusion.

Twenty minutes after the infusion had been completed

the heart rate began to slow. The patient had another

asystolic convulsion 32 minutes after termination of the

infusion. ;\ second infusion, which supplied 3 pg iso-

proterenol per minute, maintained the ventricular rate

at between 44 and 48 beats per minute except for a brief

episode of asystolc that responded to the cardiac stimu-

lator One milligram isoprotcrenol was then given intra-

muscularly every hour for 22 hours without further

seizures. The pulse rate was maintained at 40 beats

per minute during this period. Cardiac drcompensa-

tion then recurred but responded to intensified trcat-

ment. Isoprotcrenol was begun sublingually in a dose

of 20 mg every hour. and for five hours no Adams-Stokes

episodes occurred. Acute severe cardiac decompcnsa-

tion again supervened. with resultant death.

CASE 4. \V. Hrt.: a 71-year-old white male. was ad-

mitted for an inguinal herniorrhapy, and while recover-

ing from this operation began to have occasional syn-

copal attacks. He was transferred to the medical serv-

ice, where asystolic convulsions continued intermit-

tently despite atropinization. The electrocardiogram

revealed complete heart block.

After a series of asystolic convulsions, isoproterenol was

begun sublingually in a dose of 15 mg every three hours.

Because of discomfort from palpitation the dose was

reduced to 10 mg every two hours during waking hours

(upward shift of ventricular pacemaker shown in I‘isurc

2). In subscqurnt electrocardiograms the dcr.;ree of

atrioventricular block drcreascd from a 2: 1 ratio to

delayed conduction without dropprd ventricular beats.‘5

‘0

9”

Fig. 2. Case 4. Response to 15 mg isoproterenol HCl sublinguallv for a period of 105 minutes (numbers at left show minutes). Note increase in ventricular rate and upward shift of ventricular pacemaker.

‘,‘,I,: AMERICAN ,J”URNAL OF CARDIOI.O<:Y

CIhandler and Ckqper

TIME IN DAYS n In 70 30 40 50 70 80 98

“F-.7-+- I -I- Epinephrine

/ - HEART RATE

30 1 I 5 IO 15 20 25

3 doses ~ mlssed

Fig. 3. &se 5. Effectiveness of sublingual isoproterenol HCl in the treatment of the Adams-Stokes syndrome.

During thr next six months there were no furthrr

Adams-Stokes attacks. .1. bilateral cataract removal was

performed at this time without difficulty. He was later

rehospitalized with moderately severe cardiac decom-

pensation and responded poorly to the usual regimen for

cardiac failure. Due to the slow idioventricular rate in

association \lith his complete heart block the isopro-

terenol was increased to 15 mg every two hours with

minimal cardiac acceleration. About 90 minutes after

a dose of isoprotrrmol a convulsion, not accompanied

by a period of asystole. occurred. The clectrocardi-

oyram at that time Ehowrd a “slow” ventricular tachy-

catdia (8OG90). This continued throughout the night.

Thr cardiac drcomprnsation becamr increasingly

severe, resulting in death 14 hours after the sudden

changr in his condition.

hSE 5. \V. Hmn., a 76-year-old white male. was

brought to the hospital b(.cause of convulsions. Physical

examination revealed a pulse of 26 to 40 per minut?.

Jerking spasmodic motions of both legs were noted.

Electrocardiograms on different occasions revealed com-

plctc atriovrntricular block. His response to combined

therapy for heart block with ephedrine. atropine, and

epmcphrme-in-oil was rather slow. Epinrphrine-in-oil

\vas discontinued on the seventh day, and on the tenth

day a series of asystolic convulsions occurred. The re-

institution of rpinephrinr-in-oil accelerated the heart

rate to between 40 and 48 beats per minute and he

rcmainpd asvmptornatic until one month after admission.

when the rpinephrine-in-oil was again stopped. Al-

though ephedrine and tincture of belladonna were con-

tinued, another series of asystolic convulsions com-

menced that could not be adequately controlled with

aqueous epinephrine. Despite the reinstitution of

epinephrine-in-oil the convulsions continued throughout

the night.

Five weeks after admission asystolic convulsions rc-

currcd and were uncontrolled for 24 hours by the usual

medications. Sublingual isoproterenol was started at

this time in a dose of 15 mg every three hours. The

response was excellent (Fig. 3), and the electrocardi-

ogram the next morning showing completr heart block

with a ventricular rate of 60-72 per minute. No con-

c&ions or periods of asystole occurred during the next

seven weeks. Inadvertently three consecutive doses

wrre then omitted resulting in three convulsions. ISO-

protercnol was reinstituted and continued in a dose of

20 mg every two hours. No convulsions or episodes of

syncope occurred during the next five weeks. He died

from sever? cardiac decompensation three months after

the start of isoprotcrrnol therapy.

CASE 6. K. L., a 65-year-old Negro malt., had been

treated without success for his dizzy spells over a period of

three years on an outpatient basis. These spells occurred

three or four times per day. His heart rate was 30 to 36

beats per minute on frequent determinations. The

electrocardiogram revealed a complete heart block.

hlthounh the trst dose of sublingual isoproterenol did

340 Complete AV Block Treated with Isoproterenol

Fig. 4. Case 1. Development of ~‘slow” ventricular tachycardia after inadvertent subcutaneous administra- tion of 20 mg isoproterenol HCI. with spontaneous re- version to former rate.

not produce a significant response, it was decided to

treat him with 20 mg every two hours to observe the

effect on the Adams-Stokes episodes. Only one or two

mild dizzy spells have occurred during nine months of

isoproterenol therapy despite the fact that the heart

rate has increased only slightly (40 per minute).

CASE 7. N. M., a 63.year-old white male, was

admitted to the hospital because of heart failure. The

electrocardiogram revealed a rate of 28 heats per minute

and complete atrioventricular block. Maintenance

therapy with isoproterenol was begun with a dose of 20

mg every two hours with resultant increase in the heart

rate from a level of 28-30 per minute to one of 40-50.

On his first visit to the outpatient department he com-

plained of frequent episodes of dizziness and light-

headedness which initially were attributed to heart

block. Careful questioning of the patient revealed that

he had not correctly understood the instructions and had

been taking two tablets three times per day instead of

every two hours. He was reinstructed in the use of the

drug and has not had any episodes of dizziness for a

period of twenty weeks.

SIDE REACTIONS ?,ND TOXICITY

Side reactions to sublingual isoproterenol were few, considering the frequency and size of the doses. Two patients had palpitations

after receiving 15 mg, but when the dose was reduced to 10 mg given more frequently this complaint was eliminated without detracting

from the effectiveness of the medication. One patient developed a sore mouth which disap- peared while the medication was continued at the usual dosage and interval.

The majority of the patients receiving sub- cutaneous epinephrine or isoproterenol com-

plained of uncomfortable palpitations at the height of action of the drug. Only one was vociferous in his complaints.

One patient (case 1) inadvertently given 20

mg of isoproterenol subcutaneously developed a “SJOM”’ ventricular tachvcardia (Fig. 4).

The rate gradually returned to the pretreat-

ment Jevei in about five hours without an>: un-

toward effect on the patient. Patient J. W.

(case 3), who was purposelp given 2 mg sub-

cutaneously, also developed a “S~OMI” ventricular tachvcardia. The original focus regained con-

trol of the heart at the former rate in about fifty minutes.

DISCUSSKIN

Complete heart block is always associated with the danger of ventricular arrhythmia or

standstill and resultant death. The change from one focus to another, the firing off of a

rapid run of ventricular beats, either as tachv-

cardia or as fibrillation,‘~” or the transient or final loss of initiative ability of the myocardium

results in a disturbing situation of varying sevcr-

itv called the Adams-Stokes syndrome. The

treatment of this condition leaves much to be desired, and one is never certain that the pa-

tient will not escape from what appears to be

good control of the disorder. The multiplicit) of medications1,7 advocated indicates the lack

of effectiveness of any drug or combination of

drugs heretofore used.

Comparison of Isoproterenol and EjinepphrinP:

Subcutaneous isoproterenol HCl is five times

as effective as an equal dose of epinephrine in increasing the ventricular rate of patients with

complete heart block. All of our patients given isoproterenol subcutaneously had a substantial

increase in cardiac rate, but that was true of only 70 per cent of the patients given epi- nephrine. Those who responded to both medi- cations had better results with isoproterenol despite the fact that the dosage of the latter was

one-fifth that of epinephrine. Nathanson and Miller’,” tested patients with

complete heart block in much the same way as we did, with identical results. They felt that isoproterenol HCl raises the level of the focus

in the treelikc conducting tissue and that epi- nephrine tends to lower this focus. Our results

suggest th<rt both are capable of raising the level of the controlling focus. In the occasional case

in which epinephrine appeared to lolvcr the

focus, as shown by an increase in the number

of ventricular extras) stoles, isoproterenol did

not product this undesirable effect. Bizarre

ventricular complexes and occasional runs of

ventricular tachycardia were more frequent with therapeutic doses of epinephrine than

with isoproterenol. A pressor effect w-as ob-

served when the former drug was used but \vas

absent or negligible \vith the latter. ‘The safety of isoproterenol HC:l has been

shown in many animal studies.r”-‘l One

of our patients (case 1) inadvertently received subcutaneously one hundred times the rccom-

mended dose of is:oproterenol HCY. He re-

sponded with a “slow” ventricular tachycardia.

In five hours the original focus \vas again in

control. One can speculate as to the result

if one hundred times the recommended dose of

epinephrinc had been given.

Sublingml ~~ersus Subcutaneous Isoproterenol: The sublingual dose of 15 to 20 nlg isoprotcrenol

H61 used in this series was effective in 54 per

cent of those tested. Patients xvould either respond tx significant increase in heart rate to

this dose or not at all. Nathansonr had a i0

per cent incidence of response and came to the same conclusion. I’nlike the sublingual route,

the subcutaneous route produced a significant rise in heart rate in e\~er)- patient in this series

even though they had had no response to the

sublingual dose. The time of onset for the

subcutaneous route was faster in our s&e; (average four minutes) than it \vas in Nathan-

son’s (average twelve minutes), and the dura- tions of action in our group was longer (a\wage 72 minutes versus 58).

Subcutaneous administration of isoproterenol NC:1 is more consistently effective than sublin-

gual but suffers from the draw.back that fre- quent injections are required. Oral therapy, if it were as reliable, would be preferable.

Increase in the cardiac rate was much more delayed after subcutaneous epinephrine than after isoproterenol, prolrably because of delayed

absorption of the former, the result of local

MARCH, 195’)

vasoconstriction. Isoprotercnol, a vasodilator,

permitted rapid absorption. OnI>- five out of

se\en patients given epinephrine had a signifi- cant response, once action had begun. Sub-

cutaneous isoprotcrenol m-as ten times faster in

producing a rise in rate and three times faster

in reaching the peak rate, and its effect lasted

as Ion;: as that of epincphrinc.

.4lthough sut)lingual isoproterenol MCI does

not increase the cardiac rate in some cases with

heart block, it may decrease the incidence of

Adams-Stokes cpisodcs. \\‘hile conclusions can-

not hc dra\\-n from one case, it is of interest that

the heart rate of patient E. L. (case 6) was not

significantly increased hy sublingual adminis-

tration of the drug, yet during a nine-month

period of treatment Adams-Stokes attacks did

not occur. Although the drug did not acceler-

ate the rate, there may have tIeen sufficient

activation to prevent slowing of the rate.

Zntraoenous Zrrfusims: Our experience bvith the

intravenous administration of isoproterenol WC1

is limited to one patient (case 3), who wxs given

infusions on t\vo separate occasions during

periods of severe Adams-Stokes Syrdrome.

Only one asystolic convulsion, which was pre-

cipitated I)>. exertion! occurred during the course

of these infusions. Recover)- from the asystolic

convulsions \vas much faster during the infusion

than before or afterward.

(1) Sublingual isoprotercnol HC:l is effec-

tive treatment for A4dams-Stokes attacks due to

complete heart block. All patients receiving long-term maintenance therapy \verc markedly

improved

(2) Fift! -four per cent of the patients in this

series had a si,gnificant increase in cardiac rate

in response to a sutrlingual test dose of 20 mg

isoprotcrenol H(:l.

(3) Subcutaneous isoprotcrenol increases the

heart rate sooner, reaches a peak faster, and

lasts as long as a five-times-larger close of suh-

cutaneous aqueous epinephrine.

(4) Intra~cnous infusion of isoproterenol

appeared to IX effective in maintaining the heart

rate in the one case in which it was used.

(5) Isoproterenol will raise the basic focus

in some patients, stimulate the basic focus in

342 Complete AV Block Treated with Isoproterenol

the remainder, and rarely, if ever, lower the pacemaker. Epinephrine M-ill usually do the

same, hut occasionally it lowers the focus. (6) Amounts of subcutaneous isoproterenol

five, ten, and one hundred times the recom-

mended dose were given without untoward

effects, thus indicating a wide margin of safety. (7) Six of seven patients with the Adams-

Stokes s)-ndrome due to complete heart block were maintained for an average of 113 days

without convulsions or syncopal attacks by the

sublingual administration of 10 to 20 rng isopro-

terenol at intervals of two or three hours.

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2. NATHANSON, M. H. and MILIXR, H.: ‘The effect of new drugs on the rhythmic function of the heart. California .Med. 72 : 215, 1950.

3. NATHANSON, M. H. and MILLER. H.: The effect of l-( 3,4-dihydroxyphenyl) 2-isopropyl aminoeth- anol (isopropyl epinephrinc) on the rhythmic property of the human hrart. Proc. .Soc. Exper.

Bzol. &? Med. 70: 633, 1949. 4. CHANDLER, I>. and ROSENBA~M, .J. : Severe Adams-

Stokes syndrome treated with Isuprel and an arti- ficial pacemaker. .4n.. I1pnrf J. 49: 295, 1955.

5. KATZ. 1,. N.: ~~ectrocardiogrlrpf~~. Lea, Philadelphia, 1948.

6. BARKER. .I. M. : The Uni,bolnr ~lrctroccildlogrtrm, rd. 1. Appleton, NW York, 1952, p. 454.

7 FRIEDBERG, C. I(. : Di.reaws ,J/ thP Ilmrt. Saunders, Philadelphia, 1951, p. 295.

8. SCHWARTZ, S. P. and DE SOI.A POOL, N.: ‘l‘ransient ventricular fibrillation. Am. Hmrt J. 39: 361, 1950.

9. SCHWARTZ, S. P., HALLINGER, L., and IMPEKIALLI, A. : The &ects of procaine amide on patients with transient ventricular fibrillation during estab- lished auriculoventricular dissociation. Cwculu- tmn 6: 193, 1952.

10. LANDS, A. M., et al.: The pharmacology of N-alkyl homologues of epinephrine. J. Phnmmacol. B

LGper. ThmqL 90: 110, 1947. 11. KAUFMAN, J., IGLAUER, A., and HURVXZ, G. K.:

Effect of Isuprel on circulation of normal man. ilm. ./. ,\fec/. 11 : 442, 1951,

12. TAINTER, M. I,. and LANIX, A. M. : Certain actions of sympathomirnctic amincs on thr heart. ?V?Z4’ IhrX- .I. .\lrd. 53: 1433, 1953.

13. GARB, S. and CHENOWETH, M. B.: Studies on hy- drocarboncpincphrine induced ventricular fibril- lation. .f. I’f~armncol. 3 Exjer. Thm,b. 94: 12,

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14. LANDS, A. M. and HOWARD. J. W.: :I comparative study of th? vffccts of 1-arterenol, epinephrine, and isopropyl artcrenol on the heart. J. Pharmacol. ?3

.E.q~r. 7‘fwap. 106 : 65, 1952.

15. MYERS, G. 8.: Interpretatm of the Un$dar Electro-

cardiogrm. Mosby, St. Louis, 1956.

‘TEE AMERICAN JOuRNAL OF CARDIOLOGY