ISSN: 1524-4539 Copyright © 1982 American Heart Association. All rights reserved. Print ISSN: 0009-7322. Online

72514Circulation is published by the American Heart Association. 7272 Greenville Avenue, Dallas, TX

1982;66;334-338 CirculationLJ Rubin, BM Groves, JT Reeves, M Frosolono, F Handel and AE Cato

hypertensionProstacyclin-induced acute pulmonary vasodilation in primary pulmonary

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Prostacyclin-induced Acute Pulmonary Vasodilationin Primary Pulmonary Hypertension

LEWIS J. RUBIN, M.D., BERTRON M. GROVES, M.D., JOHN T. REEVES, M.D.,MICHAEL FROSOLONO, PH.D., FRANKLIN HANDEL, M.D.,

AND ALLEN E. CATO, M.D., PH.D.

SUMMARY To evaluate the effects of prostacyclin (prostaglandin 12) on pulmonary vascular tone inprimary pulmonary hypertension (PPH), we performed right-heart catheterization on seven patients withPPH and made hemodynamic measurements before and after infusing incremental doses of prostacyclin. Inmaximal doses of 2-12 ng/kg/min (mean 5.7 ± 3.1 ng/kg/min), prostacyclin reduced mean pulmonaryarterial pressure from 62 ± 15 to 55 ± 16 mm Hg (p < 0.05) and total pulmonary resistance from 17.18.7 to 9.7 + 5.9 units (p < 0.005), and increased cardiac output from 4.22 ± 1.64 to 6.57 ± 2.04 1/min (p <0.01). Heart rate increased from 83 ± 13 to 94 ± 11 beats/min (p = 0.1) and mean systemic arterialpressure decreased from 90 ± 12 to 77 ± 4 mm Hg (p = 0.055). Three patients who received a continuousinfusion of prostacyclin for 24-48 hours had sustained reductions in total pulmonary resistance during theinfusion period. These data demonstrate that prostacyclin can increase cardiac output and reduce pulmo-nary arterial pressure and resistance in PPH.

PRIMARY pulmonary hypertension (PPH) is charac-terized by extreme elevations in pulmonary vascularresistance, which ultimately result in right ventricu-lar failure and death. The cause of this disease isunknown, but prolonged vasoconstriction has beensuggested as an etiologic factor. 1-' Recent studies dem-onstrating that vasodilators such as isoproterenol,45hydralazine,6 and diazoxide7 I can reduce pulmonaryvascular resistance in PPH provide further evidencethat active pulmonary vasoconstriction may be presentand potentially reversible in some patients.

Prostacyclin (PGI2), a metabolite of arachidonicacid, is produced in vascular endothelial cells.9- 10 In-travenous prostacyclin causes pulmonary vasodilationin animals when pulmonary vascular tone is enhancedeither by hypoxiall 12 or by the infusion of ADP.'3Prostacyclin reportedly reduced pulmonary vascularresistance in a patient with persistent fetal circulation'4and in a patient with PPH, 15 and endogenous prostacy-clin may be responsible for the reduction in pulmonaryvascular tone produced by hydralazine.'6 Since intra-pulmonary platelet aggregation, as a result of the re-duced pulmonary blood flow, could further compro-mise the pulmonary circulation in PPH, the potentpulmonary vasodilator and the antiplatelet aggregatoryactions of prostacyclin'° could be beneficial in thisdisease. We therefore evaluated the hemodynamic ef-fects of i. v. prostacyclin in seven patients with PPH.

From the Department of Medicine, Duke University Medical Center,Durham, North Carolina; the Department of Medicine, University ofColorado Health Sciences Center, Denver, Colorado; and the Depart-ment of Clinical Research, Medical Division, Burroughs-WellcomeCompany, Research Triangle Park, North Carolina.

This work was performed during Dr. Rubin's tenure as an EdwardLivingston Trudeau Fellow of the American Lung Association and wassupported in part by a grant from Burroughs-Wellcome Company.

Dr. Reeves is supported by NHLBI grant HL-14985.Address for correspondence: Lewis J. Rubin, M.D., Pulmonary Sec-

tion (1 II F), Dallas Veterans Administration Medical Center. 4500South Lancaster Road, Dallas. Texas 75216.

Received August 14, 1981: revision accepted December 10, 1981.Circulation 66, No. 2, 1982.

MethodsSubjects

Seven patients with PPH entered the study after giv-ing informed consent. All seven patients had symp-toms of fatigue and exertional dyspnea, and four hadhad syncopal episodes. The diagnosis of PPH wasmade after pulmonary function studies, ventilation-perfusion lung scans and cardiac catheterization re-vealed no evidence of other causes for pulmonary arte-rial hypertension. Six of the seven patients underwentpulmonary ateriography, which showed no evidenceof thromboembolic disease. Echocardiography wasperformed on all seven patients, and none had abnor-mal left ventricular dimensions or evidence of valvulardisease. Hydrogen or green dye curves were per-formed on all patients and none showed evidence of anintracardiac shunt. The pulmonary artery wedge pres-sure was normal in all patients (mean 7 mm Hg, range4-12 mm Hg). Patient 6 had undergone a portal-sys-temic shunting procedure in 1968 for gastrointestinalbleeding associated with alcoholic cirrhosis and portalhypertension. In 1977 he was rehospitalized for uppergastrointestinal bleeding, and mesenteric angiographydocumented closure of the shunt, but he has had nofurther gastrointestinal symptoms. Two patients werebeing treated with cardiac glycosides and diuretics,which were continued during the study. The two pa-tients who were taking oral anticoagulants discontin-ued their use before hospitalization. No patient hadreceived an antiplatelet drug for 2 weeks before thestudy.

ProtocolRight-heart catheterization was performed using a

triple-lumen, balloon-tipped, flotation catheter insert-ed into a femoral or antecubital vein. A 5% dextrosesolution was continuously infused at 20-25 ml/hourthrough the right atrial port of the catheter to maintaincatheter patency and to facilitate the drug administra-tion. A polyethylene catheter was inserted into a fem-oral, brachial or radial artery for blood sampling and

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PROSTACYCLIN AND PULMONARY HYPERTENSION/Rubin et al.

pressure monitoring. Heart rate was monitored con-

tinuously. Mean arterial pressures were obtained byelectronic integration of the pressure signals. Baselinecardiac output was measured by the Fick method andby thermodilution (in triplicate) in all patients.

After control hemodynamic measurements were

made, a glycine buffer solution (vehicle) was infusedat a rate of 1 ,ul/kg/min using a Harvard infusion pump.Repeat hemodynamic measurements were made 15minutes later and the glycine buffer solution was ex-

changed for a prostacyclin solution. Prostacyclin was

infused at doses of 2, 4, 8, 10 and 12 ng/kg/min for 15minutes at each incremental dose, and hemodynamicmeasurements were made at the end of each dosageperiod. Cardiac output was measured by thermodilu-tion in all patients during the dose-ranging protocol,which was stopped at a maximal dosage of 12 ng/kg/min or earlier if systemic blood pressure decreased bymore than 30%, or if heart rate increased by more than50% compared with control or if side effects precludedan increase in dosage. Repeat baseline measurementswere made no sooner than 30 minutes after the prosta-cyclin infusion was stopped.

Three patients were maintained on a continuousprostacyclin infusion for 24-48 hours. After the maxi-mal dose was established, the patients were transferredto the cardiac care unit and repeat baseline measure-ments were made. The prostacyclin infusion was thenrestarted and gradually increased to the previously es-

tablished maximal tolerated dose. Hemodynamic mea-surements were made every 4 hours and after discon-tinuation of the infusion.

ResultsThe maximal hemodynamic effects of prostacyclin

are shown in table 1. Mean pulmonary artery pressure

decreased in six of the seven patients, and total pulmo-nary resistance decreased by more than 20% in allpatients after prostacyclin. Cardiac output and strokevolume both increased by more than 40%, while heartrate increased slightly. The mean arteriovenous oxy-

gen difference decreased from 7.4 2.0 to 4.4 2.3ml/dl. The mean systemic arterial pressure fell by morethan 5 mm Hg in only three patients.

Figures 1-4 show the hemodynamic effects of incre-mental doses of prostacyclin. Glycine buffer infusionhad no effect compared with control, but prostacyclindecreased total systemic and total pulmonary resis-tance in a dose-dependent manner. Cardiac output andstroke volume both increased. Despite marked reduc-tions in peripheral vascular resistance, heart rate in-creased by only 10-20%.

Figure 5 shows the effects of a continuous prostacy-clin infusion on total pulmonary resistance in the threepatients who were treated for 24-48 hours. Prostacy-clin produced a sustained reduction in total pulmonaryresistance during the continuous infusion in each pa-

tient. Measurements after termination of the infusionwere comparable to preinfusion control values.

Side EffectsThe development of side effects with prostacyclin

was variable and not completely dose related. Threepatients tolerated doses of 8 ng/kg/min or greater forprolonged periods, whereas the other four developed

TABLE 1. Maximal Hemodvinamic Effects of Prostacyclin IhiqusiotnDuration

ofAge symptoms SAP PAP CO HR TPR TSR

Pt (years) Sex (years) Dose (mm Hg) (mm Hg) (1/min) (beats/min) (U) (U)

1 58 M 2 Control 110 40 4.75 96 8.4 23.18 ng/kg/min 75 25 7.66 100 3.3 9.8

2 30 F 3 Control 82 50 4.76 66 10.5 17.28 ng/kg/min 77 52 9.29 102 5.6 8.3

3 21 F 3 Control 78 73 3.20 86 22.8 24.410 ng/kg/min 80 60 7.49 80 8.0 10.7

4 29 F 9 Control 86 56 3.01 98 18.6 28.64 ng/kg/min 74 53 4.57 109 11.6 16.2

5 16 F 2 Control 88 82 2.63 91 31.2 33.52 ng/kg/min 84 74 3.55 91 20.8 23.7

6 38 M 10 Control 83 58 7.43 72 7.8 11.22 ng/kg/min 78 47 7.85 80 6.0 9.9

7 38 F 2 Control 101 76 3.73 75 20.4 27.16 ng/kg/min 72 71 5.58 93 12.7 12.9

Mean ±SD Control 90 62 4.22 83 17.1 23.6±12 +15 +1.64 +13 ±8.7 +7.4

PGI, (5.7 ± 77 55 6.57 94 9.7 13.13.1 ng/kg/min) ±4 16 +2.04 +11 +5.9 ±5.4

p 0.055 < 0.05 < 0.01 0.1 < 0.005 < 0.001

Abbreviations: SAP = mean systemic artery pressure; PAP = mean pulmonary artery pressure; CO cardiac output; HR heart rate;TPR = total pulmonary resistance; TSR = total systemic resistance.

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VOL 66, No 2. AUGUST 1982

TOTAL SYSTEMICRESISTANCE

TOTAL PULMONARYRESISTANCE

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side effects at lower doses, which prevented furtherdose-ranging studies or a continuous infusion. Head-ache occurred in six patients, and was mild in three.Four patients had nausea and two had vomiting. Cuta-neous flushing was observed in five patients. Patient 4,who had a history of head trauma and pseudotumorcerebri for which a craniotomy was performed in 1967,developed diplopia at 6 ng/kg/min, which subsided 30minutes after the discontinuation of the infusion. Pa-tients 4 and 6 had systemic hypotension during thedose-ranging segment, but blood pressure returned topreinfusion levels within 5 minutes after the prostacy-clin infusion was stopped. Patient 1 had a significantreduction in systemic blood pressure during continu-

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DiscussionThe renewed interest in disorders of the pulmonary

circulation has led to the demonstration that severalsystemic vasodilators may reduce pulmonary vasculartone.'7 Our study shows that prostacyclin, one of themost potent pulmonary vasodilators, markedly re-duced pulmonary vascular resistance in a dose-depen-dent manner in all seven patients studied; this hemo-dynamic effect was sustained in several patients duringa 24-48-hour continuous infusion. These observationsdemonstrate that even in patients with severe, chronic

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CIRCULATION336

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FiGURE 3. Effect of i-,. prostaevclin on stroke volume.

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PROSTACYCLIN AND PULMONARY HYPERTENSION/Rubin et al.

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pulmonary hypertension, there is a component of ac-tive pulmonary vasoconstriction that responds to a po-tent pulmonary vasodilator.The clinical diagnosis of PPH in our patients was

based on the presence of severe precapillary pulmo-nary hypertension in the absence of demonstrable val-vular heart disease, pulmonary thromboembolism, in-tracardiac shunting, or significant parenchymal lungdisease. We have no data on left ventricular volumesor ejection fraction, so we cannot exclude the presenceof coexistent left ventricular dysfunction. It is unlikelythat left ventricular dysfunction contributed to thepresence of pulmonary hypertension in our patients,

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FIGURE 5. Effects ofa continuous infusion ofprostacyclin on

total pulmonary resistance (TPR) in three patients. Interruptedlines represent discontinuation of the infusion and subsequentcontrol measurements.

since all had a normal pulmonary artery wedge pres-sure at catheterization and a normal left ventricularchamber size by echocardiography.A major concern about instituting vasodilator ther-

apy for PPH is the risk of producing severe systemichypotension if the drug reduces systemic vascular re-sistance without affecting pulmonary vascular tone.The risk is compounded by the fact that all of thevasodilators reported to be useful in reducing pulmo-nary vascular tone are neither highly selective nor pref-erential for the pulmonary arterial bed, by the difficultyin titrating the dose of a vasodilator to the optimalhemodynamic effect, and by the prolonged duration ofeffect of several of the currently used vasodilators.Rubino and Schroeder"8 reported a patient who mani-fested no change in systemic blood pressure with incre-mental doses of i.v. diazoxide up to 180 mg, but devel-oped refractory hypotension and died after she wasgiven a bolus of 300 mg. The ability to titrate the doseof prostacyclin to the desired hemodynamic effect, itspotency as a pulmonary vasodilator, and the ability toreverse rapidly any adverse effect by discontinuing theinfusion make prostacyclin a safe agent for initial test-ing of a patient's responsiveness to vasodilators.

Three patients tolerated a continuous infusion ofprostacyclin at doses of 8-10 ng/kg/min, with com-plaints of only mild nausea or headache, whereas atlower doses, the four other patients developed moresevere symptoms that precluded further use of thedrug. Data et al. 19 recently reported that healthy volun-teers could tolerate infusions of prostacyclin at dosesup to 10 ng/kg/min for as long as 60 minutes, althoughmost subjects had side effects at doses above 4 ng/kg/min. No subject in that study could tolerate an infusionof 4 ng/kg/min for 24 hours. Three of our patients weremaintained on a continuous infusion at 8 or 12 ng/kg/min for 24 hours; compared with normals, patientswith PPH may either be more resistant to the vasculareffects of prostacyclin or they may metabolize prosta-cyclin differently.

In conclusion, prostacyclin reduced pulmonary vas-cular resistance in a dose-dependent manner in sevenpatients with severe PPH. The hemodynamic effectspersisted during a continuous 24-48-hour infusion inthree patients. Side effects, including systemic hypo-tension in two patients, were reversed rapidly by re-ducing the dosage or by stopping the infusion. Prosta-cyclin may be a useful drug in the initial evaluation ofvasodilator therapy and in the short-term managementof seriousy ill patients with PPH.

AcknowledgmentsThe authors are indebted to Drs. Lawrence Horwitz, Robert H. Peter,

and J. Greg Perkins for their support, to the personnel in the cardiaccatheterization laboratories for their assistance, and to Judy Young andBecky Rendon for their assistance in the preparation of the manuscript.

References1. Wagenvoort CA, Wagenvoort N: Pathology of Pulmonary Hyper-

tension. New York, John Wiley and Sons, 19772. Wood P: Diseases of the Heart and Circulation. Philadelphia, J

Lippincott, 1956, p 8393. Voelkel N, Reeves JT: Primary pulmonary hypertension. In Pul-

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VOL 66, No 2. AUGUST 1982

monary Vascular Disease, edited by Moser KM. New York, Mar-cel Dekker, 1979, p 573

4. Daoud FS, Reeves JT, Kelly DB: Isoproterenol as a potentialpulmonary vasodilator in primary pulmonary hypertension. Am JCardiol 42: 817, 1978

5. Shettigar UR, Hultgren HN, Specter M, Martin R, Davies DH:Primary pulmonary hypertension: favorable effect of isoproterenol.N Engl J Med 295: 1414, 1976

6. Rubin LJ, Peter RH: Oral hydralazine therapy for primary pulmo-nary hypertension. N Engl J Med 302: 69, 1980

7. Klinke WP, Gilbert JAL: Diazoxide in primary pulmonary hyper-tension. N Engl J Med 302: 91, 1980

8. Wang SWS, Pohl JEF, Rowlands DJ, Wade EG: Diazoxide intreatment of primary pulmonary hypertension. Br Heart J 40: 572,1978

9. Moncada S., Gryglewski R, Bunting S, Vane JR: An enzyme isolat-ed from arteries transforms prostaglandin endoperoxides to an un-stable substance that inhibits platelet aggregation. Nature 263:663, 1976

10. Moncada S, Vane JR: Arachidonic acid metabolites and the inter-actions between platelets and blood-vessel walls. N Engl J Med300: 1142, 1979

11. Starling MB, Neutze JM, Elliott RL: Control of elevated pulmo-

nary vascular resistance in neonatal swine with prostacyclin(PGI2). Prostaglandins Med 3: 105. 1979

12. Leffler CW, Hessler JR: Pulmonary and systemic vascular effectsof exogenous prostaglandin I2 in fetal lambs. Eur J Pharmacol 54:37, 1979

13. Hyman AL, Kadowitz PJ: Pulmonary vasodilator activity of pros-tacyclin (PGI2) in the cat. Circ Res 45: 404, 1979

14. Lock JE, Olley PM, Coceani F, Swyer PR, Rowe RD: Use otprostacyclin in persistent fetal circulation. Lancet 1: 1343. 1979

15. Watkins WD, Peterson MB, Crone RK, Shannon DC, Levine L:Prostacyclin and prostaglandin El for severe idiopathic pulmonaryartery hypertension. Lancet 1: 1083, 1980

16. Rubin LJ, Lazar JD: Influence of prostaglandin synthesis inhibitorson pulmonary vasodilator effects of hydralazine in dogs with hy-poxic pulmonary vasoconstriction. J Clin Invest 67: 193, 1981

17. Reeves JT: Hope in primary pulmonary hypertension'? (editorial) NEngl J Med 302: 112, 1980

18. Rubino JM, Schroeder JS: Diazoxide in the treatment of primarypulmonary hypertension. Br Heart J 42: 362, 1979

19. Data JL, Molony BA, Meinzinger MM. Gorman RR: Intravenousinfusion of prostacyclin sodium in man: clinical effects and influ-ence on platelet adenosine diphosphate sensitivity and adenosine3':5'-cyclic monophosphate levels. Circulation 64: 4. 1981

Prevention of Lipid Accumulation in ExperimentalVein Bypass Grafts by Antiplatelet Therapy

LAWRENCE I. BONCHEK, M.D., ILAWRENCE E. BOERBOOM, PH.D., GORDON N. OLINGER, M.D.,

JOHN R. PEPPER, M.D., JAMES MUNNS, M.D., LAWRENCE HUTCHINSON, M.D.,

AND AHMED H. KISSEBAH, M.D., PH.D.

SUMMARY The ameliorative effect of antiplatelet therapy on atherogenesis of vein grafts was assessed inautologous cephalic veins grafted into femoral arteries of 16 normolipemic and 11 hyperlipemic stump-tailed macaque monkeys. Before grafting, one half of each vein was distended at high pressure (700mm Hg)and the other half at low pressure (350 mm Hg). Eight normolipemic monkeys were treated with aspirin, 80mg/day, and dipyridamole, 50 mg/day, and eight were controls. When grafts were harvested at 12 weeks,tissue cholesterol and ,8-apoprotein content in grafts from untreated monkeys were significantly higher thanin ungrafted, uninjured veins. Antiplatelet therapy eliminated the increase in lipid content of vein segmentsdistended at low pressure, and significantly lowered lipid content of segments distended at high pressure,though not to the control levels of ungrafted veins. Seven of the 11 hyperlipemic monkeys receivedantiplatelet drugs and four did not. The lipid content of all graft segments was significantly higher than ingrafted or ungrafted veins from normolipemic monkeys. Antiplatelet therapy again significantly reducedthe lipid content in vein segments distended at both levels of pressure, and also reduced the elevatedcholesterol content in ungrafted veins. Although this animal preparation differs in many ways from humancoronary bypass operations, these observations may be pertinent to the prevention of atherosclerosis inhuman vein bypass grafts.

SAPHENOUS VEIN aortocoronary bypass grafts can de-velop atherosclerotic changes that lead to graft stenosis orocclusion. '-, 2 The pathogenesis of these atheroscleroticchanges in vein grafts is probably similar to that of

From the Departments of Cardiothoracic Surgery and Medicine,Medical College of Wisconsin, Milwaukee, Wisconsin.

Presented in part at the 54th Scientific Sessions of the American HeartAssociation, Dallas, Texas, November 18, 1981.

Address for correspondence: Lawrence I. Bonchek, M.D., Depart-ment of Cardiothoracic Surgery, Medical College of Wisconsin. 8700West Wisconsin Avenue, Milwaukee, Wisconsin 53226.

Received September 14, 1981; revision accepted December 11,1981.

Circulation 66, No. 2, 1982.

atheromata in native arteries, although the process isaccelerated. According to the most prevalent hypoth-eses about atherogenesis,3 endothelial injury exposesthe subendothelial connective tissue to platelets andother blood constituents. Platelets adhere to the suben-dothelial collagen, aggregate, and release the contentsof their granules. The massive infiltration of plateletcontents, plasma lipoproteins, and possibly otherblood components leads to focal proliferation ofsmooth muscle cells in the vessel wall stimulated by amitogenic factor released by platelets, to formation ofconnective tissue matrix, and to deposition of lipids.

Since some degree of trauma to vein grafts duringharvesting and preparation for coronary revasculariza-

CIRCULATION338

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