the use isoproterenol (isuprel) evaluation congenital...

The Use of Isoproterenol (Isuprel) in the Evaluationof Congenital Cardiac Defects

By ARTHUR J. Moss, M.D., AND EDWARD R. DUFFIE, JR., M.D.

CARDIAC catheterization continues to bethe principal means for definitive study

of a wide variety of cardiac lesions. Informa-tion essential for the selection of surgical can-didates and for their postoperative evaluationis provided by this type of investigation. How-ever, the continued search for additional lab-oratory studies is evidence that current meth-ods frequently do not provide the necessaryor desired data. One of the pitfalls of thepast has been a failure to consider that physi-ologic material gathered under resting con-ditions does not necessarily reflect circulatoryresponse to the activities of everyday life. Inrecent years this shortcoming has been par-tially overcome by studying the circulatorydynamics during physical exercise as well asduring rest.1-8

Active physical exercise can usually beaccomplished in the adult but in the infant orchild, a number of obstacles are frequentlyencountered. Chief among these are inabilityto comprehend or to carry out instructionsand an unwillingness to cooperate. Even whensuccessfully accomplished, the fear, apprehen-sion, and anxiety that prevail in the consciouschild may profoundly affect cardiac output,and this may in turn give rise to significanterrors in the interpretation of the data ob-tained.9 Since most of the catheterizationstudies now performed are in this youngerage group, the problem is one of major pro-portions.The purpose of this investigation was to

attempt to produce the physiologic alterationsof exercise by the intravenous infusion of asynthetic catecholamine, isoproterenol.* Iso-

Prom the Department of Pediatrics, Universityof California Medical Center, Los Angeles, California.Supported in part by grants HTS-5449 and 2A-

5292, U. S. Public Health Service.*Isuprel (Winthrop Laboratories, New York, New

York).

proterenol is known to produce effects similarto those of exercise in that the respiratoryrate is increased, peripheral vasodilatationoccurs, and a powerful chronotropic and ino-tropic action is exerted on the myocar-dium.10-25 Infusion of this material in dogsquite accurately reproduces the performanceof the left ventricle obtained with exercise.22

Material and MethodsObservations were made on 38 subjects, 19 male

and 19 female, ranging in age from 1 to 17 years.Half the group had previously undergone cardiacsurgery and were studied to appraise the resultsof operation. The remainder were studied fordiagnosis. With the exception of two of the olderchildren, a 10-per cent solution of Thiamylol*was administered rectally to all subjects under 12years and a 2.5-per cent solution of sodium pento-barbital intravenously to all over this age. Allwere premedicated with meperidine hydrochloride.t

Right heart catheterization was accomplishedvia the right saphenous vein in children under 5years and via the right antecubital vein in thoseover 5 years. Retrograde left heart catheterizationwas accomplished from the right braehial artery.Lehman or Goodale-Lubin cardiac catheters wereused. In 35 of the 38 cases systenmie arterial pres-sures were measured by means of an 18-gageCournand needle placed in an exposed peripheralartery. All pressures were recorded by Stathamstrain-gage transducers and an Offner multichannelrecorder. Mean pressures were measured by elec-tronic integration.The heart rate was computed from a continu-

ously recorded electrocardiogram and the respira-tory rate from the respiratory fluctuations of thepulmonary artery pressure pulse. Oxygen consump-tion was determined by the open method. Bloodoxygen saturations and contents were determinedby cuvette oximetry and by the manometric methodof Van Slyke and Neill. Cardiac outputs wereestimated by the Fick method.

Following the catheterization studies, isopro-terenol was infused into a peripheral vein in aconcentration of 0.8 microgm. per ml. of 5 per

*Surital (Parke, Davis & Co., Detroit, Michigan).tDemerol (Winthrop Laboratories, New York, New

York).

Circulation, Volume XXVII, January 1963 51

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MOI8S. Di FFIF

Table 1Effe(-t ov Isoprotereienol on Presure Relationship bet (een, Punbnonor A rtery and

Svstolic gradient(mm. Hg)

Before Duringinfusion infusion

Tetralogy of ['allot (op )Atrial septal defect (op)*Venricular septala defect op

I-st-degree atrioventrieula 1r bloeLkCause undeterminedl

Ventricular septa] defeetAtrial septa] defect (op

Pateint ductus arteriosux o0pAtrial septal defect Op

TInnocest mnurninur

Ventriicular septal Iefect-Veintrictilar septalldefect (PVentricular septal defect opPuliionic stenosisAV enitriicular septal defetetAtrial septal defect (op.I nocenit inutrmnur

C'oaretation of niain pulmonalr arter,v

Ventricular septal defeetPulmiioinic stenosis andl a trialseptal defect (op)

Aortic stenosi'SVeuitricular septaIl defectAortic steniosis andtventricular sept.-il defect,

Atrial seltal defect (of)I-nnocenit nIurnitir

Aortic stenosis*Vtenitricular septal defect (OpAtrial septal dcefect'Atrial septal defeet-

_,

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Right Ventricle

Site of predominantgradient

PlIIIIIo(1e ValvePulmornnei valve

Pulnionic valve

PIaIIlnioic VaivePa11-olouie valve

Main pulmonary arteryPulnoInie valve

Infundibulum-Pulnionic valveITnfuo(libuilunli

Pnll11oioie xa1lve

Maini pulmiIonary arteryPulmonici valvePuln-sonic valvePulmioniie valvePulmonic valve

"Ifad signiifi,lant pulmoiai( stenlosis hlenonll"-stra tel(I o1nly (1111 illg illfssiol of isoprotereniol.(op') Oper-atedl upon.

(cent dextrose solution. The rate of infusioni rangedfrom .03 to .07 microgm. per Kg. per minute,depending upon the pa-tient's size and individualresponse. Observations were made onlv after a

maximum and uniformrn response was obtained,i.e., 2 to 4 minutes.

Observations were also mrade during supineactive exercise in the two subjects who were notaniesthetized. For this purpose, a bieyele-typeergometer* was attached to the foot of the x-ray

table and measurenments were miiade after 2 immin-utes of pedaling at a rate of 56 r.p.mi., the workload being 54 ft. lb. per revolution.

*Pedicisor (Electro-Medical Enginieerinig Co., Btur-ba IJk, Californlia

ResultsThe response to isoprotereniol became steady

after the iniitial 2 to 4 minutes of infusion(heart rate, respiratory rate and arterialpressures beiing used as parameters). Toxicsvmptoms attributable to the drug itself were

not encountered. Occasionally, upon with-drawal of the (atheter into the right veim-

triele, ve imtricular premature beats occurred

as the tip traversed the outflow tract. Theywere also observed when the catlheter tip was

initiallv positionted withinl the left ventriclebut ini lno case did any prolonged or seriousarrlhthlllmia arise.

Circulation, Volume XXVII, January 1963

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ISOPROTERENOL IN' EVALUATION OP CONGENITAL DEFECTS

Table 2Effect of Isoproterenol in Aortic Stenosis

Pressure, left Pressure Systolic Per cent changeCase Age ventricle aorta gradient of restingno. (yr.) Sex State (mm. Hg) (mm. ng) (mm. Hg) gradient

Before 180/9 110/78 7020 14 M During 225/0 90/60 135 ± 93

22 8 FBefore 114/8 104/72 10

- 20During 112/1 104/70 8

2516 m ~ Before 126/0 106/60 20+825 16 M Duriing 144/-10 108/60 36 + 80

Before 144/-4 108/42 3629 16 F' During 208/-12 120/30 88 ±145

Effect of Isoproterenol on Heart Rate andRespiration

The heart rate increased in all 38 subjects,rising from a mean of 90 to a mean of 141per minute. The range of increase was from20 to 127 per cent. The respiratory rate like-wise showed a consistent increase, rangingfrom 12 to 59 per cent of the pre-infusionrate. The mean respiratory rate before iso-proterenol infusion was 18 per minute and atthe height of response, 23 per minute.Effect of Isoproterenol on Intracardiac andArterial Pressures

The effect of isoproterenol on the rightatrial pressure was recorded in 11 subjects.In nine the mean pressure decreased, in oneit remained unchanged, and in one it in-creased.

Observations on the pulmonary arterialpressures were made in 35 subjects. The sys-tolic pressure decreased during infusion in 24,increased in nine, and remained unchangedin two; the diastolic pressure decreased in23, increased in four, and was unaffected ineight; the mean pressure decreased in 27,increased in three, and was unaltered in five.Withdrawal pressure tracings from the pul-monary artery were recorded before and dur-ing isoproterenol infusion in 28 subjects(table 1). Nine had a significant systolicgradient (greater than 20 mm. Hg) acrossthe pulmonic valve during infusion of iso-proterenol, which was not detected by theusual catheterization study. Another patienthad a coaretation of the pulmonary artery in

Cireulation, Volume XXVII, January 196$

which the gradient was accentuated to a sig-nificant level by the simulated exercise.

Observations on the systemic arterial pres-sure were made in 35 subjects before and dur-ing isoproterenol infusion. The general re-sponse here also was a reduction in pressure.Although the systolic pressure decreased inonly 15, both the diastolic and the mean pres-sures decreased in 33 of 35 patients. Theeffect of isoproterenol on aortic stenosis wasalso studied (table 2). Three of the four sub-jects in this group showed a definite increasein the systolic gradient and the fourth showedno significant change.Effect of Isoproterenol on Cardiac Output

The cardiac index was estimated before andduring isoproterenol infusion in four patients,and in each case the cardiac output increased(table 3). The oxygen consumption remainedessentially the same and the arteriovenousoxygen difference narrowed in all four sub-jects. The stroke volume increased in three.

DiscussionThis investigation confirms previous reports

on the physiologic effects of isoproterenol andis the first reported application of its useful-ness to simulate exercise clinically. It in-creases the heart rate, the respiratory rate,and the cardiac output and causes the pulmo-nary and systemic vascular beds to dilate.10-25The most pronounced effect is upon the heartrate although the stroke volume does rise tosome extent. The rate rapidly increases to alevel that parallels or even exceeds that ob-

53



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MOSS, DUFFIE

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served with exercise. As opposed to exercise,however, the arteriovenous oxygen differencewith isoprotereniol narrows and the oxygeneonisumption rises olnly slightly, if at all.28Also, whereas the stroke volumnie tends to in-crease somewhat wit-h isoproterenol,23, 25, 29 itshows little or no change in niormal unitrained individuals with exercise.22 28 30, 31The peripheral vascular resistanee is re-

duced with bothl isoprotereniol and exercise,but, paradoxically, the systemrie arterial pres-sure tenids to fall in the former anid to rise inthle latter.2"3-28, 32 The basis for this is un-doubtedly a relatively greater flow with exer-cise. The miean pulmoniary arterial pressuretenids to fall with isoprotereniol when: the vas-eulature of the lungs is n:ormal. This suggeststhat isoproterenol mi-ay be of value in apprais-ing the pulhuonary vascular bed, anid studiesin this directioni are currently in progress.WTith exercise, the effect on pulmaonary arte-rial pressure is -variable; it mayv remrnain thesame may diminish, or mnay becomne mildlyelevated.33 36

The discrepanieies that exist between tilecardiopulmonary effects of isoproterenol andexercise are not inlportant so far as the use-fulness of this drug in cardiac evaluation isconeeriled. The principal desired effect is aninierease in cardiae output, anid this isachlieved by both.1 2, 13, 23, 25-29, 31, 32, 35, 37, 38 A

more pronounced response imiail be obtained,however, with an extreme degree of exercisebut this degree is rarely attained under theusual conditions of the catheterizatioil labo-ratorv. The strikinig siniilarity of response(lenlon-istrated by comparative studies of iso-proterenol aild moderate exereise in two individuals is illustrated in figure 1.

TIhe observed fall in riight atrial pressureis ill ag'reement Awith findings reported byothlersI "'" This fall probably is nlot due toa change in thie iiltrapleural pressure, sineEckstein amii( Hamilton3"'' lhave shown- thatthe esophageal pressure does inot fall withthe administratioll of isoproterenol. It nmaybe a refleetion-i of illereased enlptying of theriglit ventricle due to the iniotropic effect ofthe dru(g

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ISOPROTERENOL IN EVALUATION OF CONGENITAL DEFECTS

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The results of the present investigation sug-

gest that isoproterenol has its greatest appli-cation in the appraisal of obstructive valvu-lar lesions. Nine subjects were found to havea mild but significant degree of pulmonic ste-nosis, which became apparent only after theinfusion of isoproterenol. Four of these ninewere postoperative patients, three of whomwould have been considered completely cor-

rected. A retrospective review of the phono-cardiograms of these patients revealed evi-dence compatible with this diagnosis in six


of them. Of the remaining three patients, one

had a ventricular septal defect and one aorticstenosis, and evidence of associated pulmonicstenosis may thus have been obscured.

In one patient an obstruction was found inthe main pulmonary artery during the infu-sion of isoproterenol. This was demonstratedby angiocardiography to be due to coarcta-tion of the main pulmonary artery.Four patients with clinically apparent aor-

tic stenosis were studied, and isoproterenolaccentuated the systolic gradient in three. The

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gradient was sufficient in two eases 20 anid29) to warrant operative intervention. In the

fourth (case 22), only a mild defgree of ob-struction was demonstrated, and failure ofisoprotereniol to accentuate the gradient inthis patienit was iiiterpreted as evidence of a

good prognosis. This ehild was aecordinglvpermitted full utnrestrieted activ-it.v

SummaryIsoproterenol was infused intravenouslx at

a rate of 0.03 to 0.07 ug. per Kg. per minute in38 patients undergoing cardiae catlieteriza-tion to evaluate the routine postoperative eoii-

ditiorn of 1.9 patients and to support or coil-

firni the clinical diagnosis in 19 others.A steadv response was obtained in 2 to 4

ninlutes, and nro toxic effects were obser-ved.During the infusioni the heart rate inereasedan average of 55 per cent; the respiratoryrate, 23 per cent. The right atrial pressure

fell. In general the pulmonary and systemiearterial pressures also decreased. Limited ob-servations on the cardiac outpult confirmedthe previously reported increase. Ten patientsdeveloped a significant systolic gradient be-tween the right Aentricle and pulmonaryartery (greater than 20 mm. Hg) during theinfusioin. Four of these were postoperativepatients, three of whoml were considered com-

pletelx corrected prior to infusion of the iso-proterenol. Four patients with aortic stenosiswere studied. and the systolic gradient in-creased in three (80, 93. and 145 per cent).The results indicate that infusion of iso-

protereinol is a safe, practical, and effectivemeans of simulatinog exereise in infants andchildren. Used in addition to the customary-cardiac catheterization studies, it is of dis-

tinet value in appraising congeneital cardiacdefects.

AcknowledgmentThe authors are grateful to Drs. John Adam>s,

Forrest Adams, and Victor Hall, for their help in

the preparation of this manuscript.

References1. 11I('CKAM, J. 13., AND CARGILL, W. H.: Effect

of exercise on cardiac output and pulmonaryarterial pressure in normal persons and in

patients with cardiovascular disease and pul-

monary emnphysema. J. Clin. Invest. 27: 10,1948.

T.AMNIxIN, H. T., AND SWAN, H. J. C.: Arterialdilution curves of T-1824 (luriing rest andexercise. Fed. Proe. 12: 93. 19.53).

O. BRICE, B. A., AxMD JoT-N, G. (G.: Effects of ui p-

r-iglht postuire and exercise pilmonary hemo-

disnamies in patients witl eertral earliovnseu-lnr shlunts. Circulation 16: 776, 1957.

4. SNVAN-, T1. J. C., TARsuALrL, HT. W.. xx\i) WooD,

F. H.: The effect of exercise ini the siupineposition on pulmonary vaseiular d-ynamics inpatienits wvith left-to-riglit simuits. T. Cli(TTInest. 37: 202, 1958.

IKKOS, P., WALLGIREN ., ANTD ZrTTFRQVIST, P.:Conaretation of the aorta: n postoperative fune-tional studx. Acta p1med4it. (T.pp, 48: 353,19.59.

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7 BECK, W., SXA-,, TT. J. C., XI3RCTELI., H. B.,

ANID KIRKLIN, J. W.: Puilmonary vascularresistance after repair of atrial septal defectsin patients with pulmoary hfiypertension. Cir(lilation 22: 938, 1960.

S. TKKOS, I., RvnnTEx, 1T., WNLLGREN, CT., ANNI

ZETTERQVTST, P.: Coaretation of the aorta.:A postoperative funetional and nanatomicalstudlvy. Cardiologia 37: 270, 1960.

9). SrTxD, E. A.. JRa., WARRERN, J. V., \TERRITjL, A. ..,

AND BR.XNNoNT, E. S.: The ca-rdiac output in

male subjects as me,a.sured bv the technique ofright atrial catTleterizati on. Normal Values withobservations on the effect of anxiety andtilting. J. Ulin. Invest. 24: 326, 1945.

10. LAxnS, A. M., NASH, V. L.,T MCCARTHY, H. M.,

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ISOPROTERENOL IN EVALUATION OF CONGENITAL DEFECTS

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ARTHUR J. MOSS and EDWARD R. DUFFIE, JR.Defects

The Use of Isoproterenol (Isuprel) in the Evaluation of Congenital Cardiac

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