,3-Adrenergic stimulation of the failing ventricle: a

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1 THRAPY AND PRVNTION CONGSTIV HART FAILUR,3-Adrenergic stimultion of the filing ventricle: double-blind, rndomized tril of sustined orl therpy with prenlterol GARY S. ROUBIN, M.B., CHRISTOPHR Y. P. CHOONG, M.B., SUSAN DVNISH-MARS, B.Sc., NORMAN N. SADICK, M.B., PH.D., PTR J. FLTCHR, M.B., PH.D., DAVID T. KLLY, M.B., AND PHILLIP J. HARRIS, M.B., D.PHIL. ABSTRACT leven ptients with severe left ventriculr impirment (men ejection frction 24%) nd moderte impirment of exercise tolernce underwent double-blind, plcebo-controlled, crossover tril of the orlly dministered /3-gonist prenlterol. xercise hemodynmics nd tolernce were mesured during bicycle nd tredmill exercise fter 2 weeks of therpy with plcebo or prenlterol. Crdic index, ejection frction, nd stroke work index were not improved nd exercise durtion nd pek oxygen consumption were not significntly different during the two tretments. During prenlterol tretment hert rte during exercise ws consistently reduced. These results show tht prolonged therpy with prenlterol does not improve hemodynmics or exercise tolernce nd is ssocited with diminished hert rte response to exercise. Circultion 69, No. 5, , SHORT-TRM dministrtion of orlly ctive l3- drenergic gonists improves hemodynmics in ptients with hert filure both t rest nd during exercise.' - However, doubts exist s to the bility of the impired ventricle, lredy exposed to incresed sympthomimetic ctivity, to respond to dditionl longterm drenergic stimultion.68 There hve been no well-controlled trils of prolonged 8,3-gonist therpy in ptients with hert filure. This study ws designed to exmine the effects of 2 weeks of orl therpy with the /3-gonist prenlterol on left ventriculr function, exercise hemodynmics, nd exercise tolernce in mbulnt ptients with modertely severe left ventriculr impirment. Methods Ptient selection. leven ptients with chronic left ventriculr filure (>3 months durtion) due to congestive crdiomyopthy (six ptients) or previous myocrdil infrction (five ptients) were studied. Their men ge ws 51 yers (rnge 27 to 59). Clinicl detils re shown in tble 1. Men rdionuclide left ventriculr ejection frction before entry into the study ws 24% From the Hllstrom Institute of Crdiology, Royl Prince Alfred Hospitl nd Deprtment of Medicine, University of Sydney, Sydney, Austrli. Supported by grnts from the Ntionl Hert Foundtion of Austrli nd the Postgrdute Committee of the University of Sydney. Address for correspondence: Phillip J. Hrris, M.B., Hllstrom Institute of Crdiology, Royl Prince Alfred Hospitl, Missenden Rd., Cmperdown, N.S.W. 25, Austrli. Received July 15, 1983; revision ccepted Feb. 2, Vol. 69, No. 5, My 1984 (rnge 16% to 32%). All ptients were New York Hert Assocition functionl clss II or I1l nd on tredmill exercise testing hd n estimted pek oxygen consumption equl to or less thn 6% of tht predicted for helthy subject of similr ge. 9 In ll ptients exercise ws limited by dyspne, ftigue, or both. No ptient suffered chest pin or hd evidence of exercise-induced myocrdil ischemi nd ll were in sinus rhythm. Study protocol. All ptients were studied s outptients nd gve written informed consent. After 2 week stbiliztion period, ptients entered dose-rnging phse in which prenlterol1 ws given in n initil dosge of 5 mg every 12 hr. After 4 dys ptients were ressessed nd in the bsence of dverse findings or side effects, the dosge ws incresed to 1 mg every 12 hr. The ptients were gin ressessed on dy 8. ight ptients were ble to tolerte the drug t the higher dosge. The remining three ptients tolerted only 5 mg bd due to sinus tchycrdi (one ptient), incresing frequency of ventriculr ectopic bets (one ptient), nd unplesnt plpittions (one ptient). A 1 week wshout period then followed, fter which ptients were rndomly ssigned to receive either plcebo or ctive drug t the pproprite dosge. After 2 weeks of orl therpy ptients hd further 1 week wshout period nd then received the lterntive tretment. Ptients were studied on the lst dy of ech tretment phse. Digoxin ws stopped in ll ptients before the stbiliztion period, but diuretics nd vsodiltors (three ptients) were continued (tble 1). On both study dys, blood levels were mesured 2 hr fter ingestion of prenlterol or plcebo. The men plsm concentrtion of prenlterol ws 231 nmol/liter (rnge 81 to 438). xercise nd hemodynmic ssessment. On the morning of ech study dy, diuretics nd vsodiltors were withheld nd ingestion of drug ws supervised. A rdil rteril cnnul nd No. 7F Swn-Gnz thermodilution ctheter were inserted percutneously in 1 of the 11 ptients. One ptient underwent exercise testing nd rdionuclide studies without invsive 955

2 ROUBIN et l. TABL 1 Clinicl chrcteristics LVF Ptient Age (yr)/sex Dignosis (%) Mediction/dy 56/M Anterior Ml 22 Furosemide 4 mg 27/M Idiopthic C/M 2 Hydrochlorothizide 5 mg Amiloride 5 mg 3 59/M Idiopthic C/M 21 Hydrochlorothizide 5 mg Amiloride 5 mg 4 59/M Anterior & inferior Ml 16 Furosemide 4 mg 5 53/M Idiopthic C/M 27 Furosemide 4 mg 6 53/M Alcoholic C/M 2 Furosemide 4 mg 7 49/M Alcoholic C/M 3 Furosemide 4 mg Isosorbide dinitrte 4 mg 8 55/M Alcoholic C/M 31 Furosemide 4 mg Spironolctone 1 mg Isosorbide dinitrte 4 mg Przosin 1.5 mg 9 55/F Idiopthic C/M 31 Furosemide 4 mg Spironolctone 15 mg 1 41/M Anterior MI 2 Furosemide 8 rmg Amiloride 1 nig Isosorbide dinitrte 8 mg ll 55/M Anterior MI 32 Hydrochlorothizide 5 mg Amiloride 5 mg Ml = myocrdil infrction; C/M = crdiomyopthy; LVF left ventriculr ejection frction. hemodynmic monitoring. xercise testing ws performed on bicycle ergometer fter 1 hr rest period (2 hr fter ingestion of drug). A tredmill hemodynmic exercise test ws performed fter nother 2 hr rest. Bicycle exercise. Rest nd exercise mesurements were performed in n ir-conditioned lbortory with the ptient positioned semiupright on n exercise tble (Atomic Products, New York) set t 45 degrees to the horizontl nd equipped with n electroniclly brked bicycle ergometer (Siemens-lem 38B). During exercise, hert rte, electrocrdiogrm from led CM5, phsic nd men (by electronic dmping) rdil rteril pressures, pulmonry rteril pressure, nd right tril pressure were recorded continuously. Pulmonry rteril wedge pressure ws recorded during the lst 3 sec of ech exercise level. When stisfctory wedge pressure could not be obtined, the pulmonry rteril distolic pressure ws used for comprison between the two studies. The zero reference point for pressures (Bell nd Howell trnsducers) ws set t the fourth intercostl spce in the midxillry line nd recorded on n lectronics for Medicine VR- 12 recorder. xercise ws limited by symptoms, with the worklod commencing t 15 W nd incresing by 15 W every 3 min. A 12-led electrocrdiogrm ws recorded every minute. Crdic output ws mesured by thermodilution with ice-cold 5% dextrose nd ws clculted with n Instrumenttion Lbortory Computer (Model 7 1). Five mesurements were mde t rest. During exercise, t lest three mesurements were mde in the lst 1.5 min of ech 3 min exercise level. Stroke volume, stroke work index, nd systemic vsculr resistnce were clculted with stndrd formuls.1' Rdil nd pulmonry rteril blood smples were collected t rest nd t the end of ech exercise level for mesurement of oxygen sturtion. The rdil rteril smple ws lso used for mesuring hemoglobin t rest nd during exercise. The rteriovenous oxygen content difference ws clculted s 1.39 X (the 956 difference between rdil rteril nd pulmonry rteril oxygen sturtions) X hemoglobin level.'2 Oxygen consumption ws clculted s the crdic output x rteriovenous oxygen content difference. Rdionuclide ventriculogrphy. Multiple-gted equilibrium rdionuclide ventriculogrphy ws performed fter lbeling of red cells in vivo with technetium-99m. Imging ws performed with ptients in modified left nterior oblique position by n Ohio nucler gmm cmer (Sigm 42) equipped with 3 degree slnt hole nd high-sensitivity collimtor nd interfced to PDP- 1 1 computer. Counts were collected for 6 min t rest with simultneous recordings of intrvsculr pressures nd crdic output. During exercise, counts were collected in the lst 2 min of ech 3 min stge. The composite crdic cycle ws divided into 24 frmes for nlysis by vrible region of interest. Left ventriculr ejection frction ws clculted from the bckground-corrected time-ctivity curve. Stroke volume ws determined from the thermodilution Crdic output nd expressed s stroke volume index. nd-distolic volume ws clculted by dividing the thermodilution stroke volume index by the rdionuclide ejection frction nd ws expressed s the end-distolic volume index. nd-systolic volume index ws clculted s end-distolic volume index minus the stroke volume index. This method of mesuring bsolute left ventriculr volumes hs been vlidted in 1 ptients. Thermodilution crdic output nd rdionuclide ejection frction were mesured with ptients in the supine position nd the derived end-distolic volumes (thermodilution stroke volume/rdionuclide ejection frction) were correlted with their corresponding end-distolic volumes clculted from single-plne cinengiogrphic studies by the re-length method of Kennedy et l.'3 Derived end-distolic volume ws equl to 1. 1 ngiogrphic end-distolic volume + 13 ml (r =.94, p <.1). The reproducibility of derived enddistolic volumes t rest nd on exercise ws tested 2 dys prt. CIRCULATION

3 THRAPY AND PRVNTION-CONGSTIV HART FAILUR Li. uj -J 4 L 21 O 3 I (P:NS) P 2[ [ n. 1g..- C Prenlt'erol.X 11 F JN- (P NS) (p=ns) e..r 1 (P:NS) FIGUR 1. Individul nd group men hemodynmic vlues obtined with ptients resting in semiupright posture during plcebo nd prenlterol tretments. LVF = left ventriculr ejection frction; HR = hert rte; PAWP = pulmonry rteril wedge pressure; CI = crdic index. The men difference in observtions mde t rest ws % ( SD) (n = 13) nd tht in observtions mde during exercise ws % (n = 13). Tredmill exercise. Tredmill exercise (Avionics Delmr C16) ws performed ccording to modified Nughton protocol'4 nd the work level ws incresed every 3 min. Hemodynmic prmeters were mesured continuously by mens of pressure trnsducers positioned on the hndril of the tredmill, with the sme reference point s for bicycle exercise. xercise ws limited by symptoms s determined from hemodynmic mesurements nd blood gs nlyses mde t ech work level. Sttisticl nlysis. Results re expressed s men + 1 SD. l-emodynmic mesurements t rest nd exercise with ptients on ctive tretment were compred with the results of the plcebo rest nd exercise studies by three-wy nlysis of vrince. c 3: C,,1, : 3. -cc C: 4 2 L 2_ 1_ 3, 2 1 OL.( p) N ( p - NS J A.. -- Vol. 69, No. 5, My CU ) cs C1 c F w< P9 < [ (p: NS) 4 Pc Pe t epr 14 (p-ns) When there ws significnt interction between drug therpy nd exercise level, ctive tretment nd plcebo studies were compred seprtely t rest nd during exercise by t sttistic derived from the pooled error men squre. The t vlue required for two plnned comprisons ws pplied ccording to the Bonferroni method, with p <.5 defined s significnt. Results Resting hemodynmics. Resting hemodynmic vlues obtined before bicycle nd tredmill exercise tests re shown in figures 1 nd 2. The resting left ventriculr ejection frction ws similr during the prenlterol nd plcebo phses. Crdic index t rest, with ptients in FIGUR 2. Individul nd group men hemodynmic vlues obtined with ptients resting in upright posture during plcebo nd prenlterol tretments. SWI = stroke work index: HR = hert rte: PAWP = pulmonry rteril wedge pressure; Ci - crdic index. 957

4 ROUBIN et l. TABL 2 Comprison of hemodynmics t rest nd during mximum exercise SVR HR (bpm) MAP (mm Hg) CI (I/minim2) RAP (mm Hg) (dyne-sec-cm 5) SVI (m1/m2) Rest x Rest x Rest x Rest x Rest x Rest x Bicycle Pren B ± ± ±9 Plc ±14 ±.3 ±1.7 ±1 ± Tredmill Pren A ± 11 ± 19 ±.5 ±+1.4 ± 1 ± Plc ±19 ±11 ±15 ±.3 ±1.4 ±2 ± ± ±8 Dt expressed s men + SD. Pren = prenlterol; Plc plcebo; x mximum exercise level; HR - hert rte; MAP - men rteril pressure; CI crdic index; SVR systemic vsculr resistnce; SWI = stroke work index; SVI = stroke volume index; F ejection frction; DVI = end-distolic volume index; SVI = end-systolic volume index; PAP men pulmonry rteril pressure; PAWP pulmonry rteril wedge pressure; RAP = = right tril pressure; AVOD = rteriovenous oxygen content difference. Sttisticl comprisons (prenlterol vs plcebo): Ap <.5; Bp <.1. both the semiupright nd upright postures, ws the sme with both tretments. Pulmonry wedge pressure ws unchnged with ptients in the semiupright posture but ws slightly reduced during prenlterol tretment before tredmill exercise. There were no differences in hert rte, men rteril pressure, stroke work index, nd systemic vsculr resistnce between the two tretment phses (tble 2). o, w ẇic W cn w ii cc *t , 2 L 151[.. 1p 5 4r R ST BICYCL _ tp - no 7 BICYCL.e * *_e A PAK : I- - (P NS) Pren Pren lterol lterol _ 4, 3~ 2 p 1 L o TRADMILL ( p. NS.--.i RST TRADMILL xercise cpcity (figure 3). xercise ws stopped in ll ptients becuse of dyspne, leg ftigue, or both. Leg ftigue ws the predominnt symptom on bicycle exercise. Durtions of exercise were similr during the prenlterol nd plcebo phses: bicycle (15.88 ± 7.1 vs min; p = NS) nd tredmill (24.49 ± 6.9 vs min; p = NS). Pek oxygen consumption chieved during tred- PAK (P -NS) P ren Pf n lterol lterol FIGUR 3. Comprison of exercise tolernce nd pek oxygen consumption (V2) during bicycle nd tredmill exercise. CIRCULATION

5 THRAPY AND PRVNTION-CONGSTIV HART FAILUR TABL 2 (Continued) AVO.D SWI (g-m/m2) PAWP (mm Hg) PAP (mm Hg) (mi/1 ml) F (%) DVI (mi/n,2) SVI (mi/m2) Rest x Rest x Rest x Rest x Rest x Rest x Rest x B A X ll ±6 ± ±1 11±I11 ± ±5 ± " 24A ±7 +15 ±6 +8 ±6 +9 ± 1.5 ± X X + I I + I mill exercise ws not chnged during prenlterol tretment(19.9 ± 6.vs ml/min/kg;p = NS). Pek oxygen consumption chieved during bicycle exercise ws lso similr during the prenlterol nd plcebo phses (17.4 ± 6.4 vs 16.8 ± 6.1 ml/min/kg) but both were significntly less thn tht chieved on the tredmill (p <.1). Mximum peripherl oxygen extrction mesured by the rteriovenous oxygen content difference did not differ between tretments either on tredmill (15.3 ± 3.4 vs 15.6 ± 1.9 ml/l ml) or bicycle ( vs 13.9 ± 2.7 ml/1 ml). xercise hemodynmics. Hemodynmic vlues obtined t the mximum worklod chieved during bicycle exercise re shown in figure 4. Mximum exercise ejection frction, crdic index, nd stroke work L LiI j -c 6, 41 2 o : 2ZD (pzns) index were similr during the prenlterol nd plcebo phses. During prenlterol tretment there ws significnt reduction in hert rte t mximum worklod nd this ws ssocited with n increse in both enddistolic ( vs ml/m2; p <.1) nd end-systolic volumes ( vs ml/m2; p <.5) nd smll increse in stroke volume (figure 5). There ws no significnt difference between tretments in pulmonry rteril wedge pressure, right tril pressure, men rteril pressure, nd systemic vsculr resistnce (tble 2). Hemodynmic vlues obtined t the mximum tredmill exercise level re compred in figure 6. Crdic index t mximum worklod tended to be lower during ctive tretment nd ws ssocited with sig- -3- (p:ns) X v (p. NS) P P Vol. 69, No. 5, My 1984 n. D 7._ ci 16 r p (p<co-1) (p:ns) FIGUR 4. Comprison of hemodynmic vlues obtined t pek worklod during bicycle exercise. Individul nd group men vlues for plcebo nd prenlterol tretments re shown. LVF = left ventriculr ejection frction; HR = hert rte; PAWP = pulmonry rteril wedge pressure; CI = crdic index. 959

6 ROUBIN et l BICYCL PAK XRCIS 25, 2 k N W 2 L 15 v. 1 L ot * PLAC w- tp.o1) 6 PRN W 15 F L PLAC (p. O5) PRN FIGUR 5. Comprison of left ventriculr volumes t pek worklod during bicycle exercise. Individul nd group men vlues for plcebo nd prenlterol tretments re shown. DVI = end-distolic volume index; SVI = end-systolic volume index: SVI = stroke volume index. 5 [ *- C.4 L *-. o3= : 3 2 (p.o.82) T PLAC PRN nificnt reduction in mximl hert rte ( vs ; p <.5). Stroke work index ws the sme during both phses. Pulmonry rteril wedge pressure ws slightly lower t mximl worklod during prenlterol tretment, but men rteril nd right tril pressures nd systemic vsculr resistnce were unchnged (tble 2). In contrst to tht observed during bicycle l ) 3: CO 3: e 3 & 2 (p: NS) A 4. 3 p 2 1t (plco 1 16 C~ v 12 m. C 8 ' 8 c6 _~ 4 U ( pe 5) (pns) exercise with ptients in the semiupright posture, the lower mximum hert rte ws not ssocited with n increse in stroke volume index. Discussion In this double-blind, plcebo-controlled, crossover tril in ptients with crdic filure, 2 weeks of orl Prenltewol FIGUR 6. Comprison of hemodynmic vlues observed t pek worklod during tredmill exercise. Individul nd group men vlues for plcebo nd prenlterol tretments re shown. SWI = stroke work index; HR = hert rte; PAWP = pulmonry rteril wedge pressure; Cl = crdic index. CIRCULATION

7 THRAPY AND PRVNTION-CONGSTIV HART FAILUR,8-drenergic receptor stimultion with prenlterol did not improve left ventriculr function, exercise hemodynmics, or exercise tolernce. These negtive results emphsize the importnce of ssessing these gents with such protocol nd of studying prolonged therpy. The plsm levels of prenlterol obtined in this study re similr to those observed with infusions of 5 to 1 g/kg body weight,15 which in short-term studies hve produced mrked improvement in rest nd exercise hemodynmics nd left ventriculr function in ptients with hert filure.' In norml subjects, sustined-relese prenlterol tblets hve been reported to produce the sme short-term hemodynmic effects s intrvenous dministrtion.' There hve been few trils of sustined orl therpy. In single-blind study ssessing 1 to 2 weeks of orl therpy with prenlterol, Hjlmrson et l.'7 found significnt improvement in echocrdiogrphic estimtes of left ventriculr contrctility nd most ptients hd improvement of symptoms. Significnt reductions in exercise hert rtes on ctive tretment were lso noted. In contrst, we found tht left ventriculr performnce ws not improved either t rest or during exercise. Resting ejection frction, crdic index, nd stroke work index were not improved with ptients in either the upright or the semiupright posture. Pulmonry rteril wedge pressure ws slightly reduced by prenlterol during tredmill exercise but this ws not observed during bicycle exercise, which emphsizes the vrying hemodynmic responses seen when ptients exercise in different postures. Despite the presence of severe left ventriculr dysfunction nd poor exercise tolernce, two ptients ppered to hve unchrcteristiclly low filling pressures, which my hve prevented n improvement in hemodynmics. Inclusion of these ptients is unlikely to hve obscured the effect of the drug on the group results, since both showed smll increse in crdic index with prenlterol. Crdic index t high work levels tended to be lower on the tredmill during prenlterol tretment becuse of the reduction in hert rte. During bicycle exercise neither ejection frction nor stroke work index were improved, but in contrst to observtions mde during tredmill exercise, the reduction in hert rte t high worklods ws ccompnied by n increse in left ventriculr volumes nd crdic index ws unchnged. The difference between the two forms of exercise my be explined by the higher left ventriculr filling pressures during bicycle exercise. Although the increse in end-distolic volume t pek exercise ws probbly relted to the reduction in hert rte,2' 21 the increse in end-systolic volume in the bsence of n increse in rteril pressure suggests tht myocrdil contrctility my hve been depressed. A similr increse in left ventriculr volumes during exercise hs been reported in ptients with left ventriculr dysfunction who were treted with /3-drenergic blocking drugs,22 but hert rte decresed nd volumes incresed t rest, n effect not seen with prenlterol. In this study the pprent decrese in left ventriculr function t pek exercise with prenlterol ws not seen in the ejection frction response nd confirms tht ejection frction is n insensitive mesure of left ventriculr dysfunction in ptients with hert filure nd lrge left ventriculr volumes.23 Our findings re consistent with those of Colucci et l.,6 who found tht short-term hemodynmic benefits with the 32-gonist pirbuterol were not mintined fter 3 dys of therpy. Not unexpectedly, the chnges observed in exercise hemodynmics were not ssocited with improved exercise cpcity. Tredmill exercise ws performed becuse it provides better ssessment of exercise tolernce nd mximl oxygen consumption, prticulrly in the ptient with crdic filure who develops erly leg ftigue on the bicycle ergometer. Although tredmill exercise time tended to be prolonged during prenlterol therpy, pek oxygen consumption ws unchnged. This disprity emphsizes the importnce of mesuring oxygen consumption s n objective indictor of erobic cpcity. The predominnt hemodynmic effect of prenlterol in our study ws inhibition of exercise-induced tchycrdi. In niml experiments prenlterol hs hd bout 7% of the intrinsic ctivity of isoproterenol on /3-drenoceptors nd could be clssified s prtil gonist with (3-ntgonist effect.'8 In short-term studies (3-ntgonist effect with reduction in hert rte hs not been seen, nd significnt increse in exercise hert rte ws reported when high doses of the drug were used.' '5 A study by Hjlmrson et l.'7 is the only one to report reduction in exercise hert rte fter 2 weeks of orl tretment with dosge lower thn tht in the present study. The difference between short- nd long-term exposure to prenlterol my be explined by the redjustment of utonomiclly medited reflex chnges with prolonged exposure. Ptients with crdic dysfunction hve n impirment of utonomic hert rte control,24 probbly cused in prt by reduction in the number nd sensitivity of (3-receptors,6, 7 ssocited with longterm elevtion of endogenous ctecholmines. It is Vol. 69, No. 5, My

8 ROUBIN et l. possible tht further sustined /S-drenoreceptor stimultion could bring bout dditionl downgrding of,/-receptors in the filing myocrdium nd further impir the lrgely drenergiclly medited tchycrdi seen t pek exercise. Colucci et l.6 demonstrted tht long-term,3-drenergic therpy in ptients with hert filure produced reduction in the,b-drenergic receptor density of the lymphocytes, but doubts hve been expressed bout the vlidity of extending these observtions to receptors in crdic tissues.25 Bristow et l.7 found tht /3-drenergic receptor density ws reduced by 5% in the filing ventricles of trnsplnt recipients when compred with tht in donor herts. In niml experiments26 4 dys of continuous drenergic stimultion produced evidence of /3-drenoceptor down-regultion, with prllel shift to the right of the concentrtion-response curves to isoproternol nd complete suppression of response to prenlterol. In the present study, fter 2 weeks of prenlterol therpy, ptients with hert filure hd diminution of the drenergiclly medited hert rte response of exercise nd n pprent decrese in left ventriculr contrctility, which my be explined by downgrding of crdic drenergic receptors or prtil /3-ntgonist effect not seen with short-term dministrtion. In contrst to results of short-term studies, our findings showed tht orl,3-drenergic stimultion with prenlterol in ptients with hert filure did not improve exercise hemodynmics or exercise tolernce. The diminution of hert rte response to exercise fter 2 weeks of therpy ppered to be cused by reduced response to endogenous drenergic stimultion. We grtefully cknowledge the expert ssistnce of Ms. ric Sinsbury, B.Sc., in nlyzing plsm prenlterol levels, Dr. Brin Comerford for ssistnce nd dvice, nd Ms. Rn Pike for her secretril skills. References 1. Wgstein F, Reiz S, Ariniego R, Hjlmrson A: Clinicl results with prenlterol in ptients with hert filure. Am hert J 12: 548, Weber KT, Andrews V, Jnicki JS: Crdiotonic gents in the mngement of chronic crdic filure. Am Hert J 13: 639, Awn NA, verson MK, Needhm K, et l: Hemodynmic effects of orl pirbuterol in chronic severe congestive crdic filure. Circultion 63: 96, rbel R, Meyer J, Lmbertz H, et l: Hemodynmic effects of prenlterol in ptients with ischemic hert disese nd congestive crdiomyopthy. Circultion 66: 351, Fitzptrick D, Ikrm H, Nicholls G, spiner : Hemodynmics, hormonl nd electrolyte responses to prenlterol infusion in hert filure. Circultion 67: 613, Colucci WS, Alexnder RW, Willims GH, et l: Decresed lymphocyte bet-drenergic receptor density in ptients with hert filure nd tolernce to the bet-drenergic gonist pirbuterol. N ngl J Med 35: 185, Bristow MR, Ginsburg R, Minobe W, et l: Decresed ctecholmine sensitivity nd bet-drenergic receptor density in filing humn herts. N ngl J Med 37: 25, Willerson JT: Wht is wrong with the filing hert? N ngl J Med 37: 243, 1982 (ditoril) 9. 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