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Acute hemodynamic effects of prostacyclin in 65 primary pulmonary hypertension patients
127
ABSTRACTS
TITLE:
ACUTI~ IIEMODYNAMIC EFFECTS OF PROSTACYCLIN HYPERTENSION PATIENTS
IN 65 PRIMARY P U L H O N A R Y
AUTHORS;
W. Long. M.D., R. Barst, M.D., A. Flshman, M.D., B. Groves. M.D., M. Frosolono, Ph.D.. K. Moser, M.D., H. Palevsky. M.D., J. Reeves, M.D., L. Rubln, M.D., A. Cute, M.D., Ph.D.
AFFILIATION : Division of Clinical Research, Wellcome Re~,earch Laboratories, Research Triangle Park, North Carolina 27577
Primary pulmonary hypertension is a poorly understood disorder in which elevations in pulmonary vascular resistance lead to progressive right ventricular dysfunction, exorcise intolerance, syncope, and death. Interest in vasodilator therapy for primary pulmonary hypertension remains high; approximately one quarter of primary pulmonary hypertension patients appear to .benefit (1), It appears that primary pulmonary hypertension patients who ~espond to vasodilators with increased cardiac output and decreased pulmonary arterial pressures have a better prognosis (1,21, but whether the better prognosis is due to actual treatment with vasodllators is doubted by some investigators (2}. ~In any case, va.Qodilator therapy can be llazardous in primary pulmonary hypertension patients with fixed pulmonary vascular beds, both acutely {3-5) and chronically, Several reports have indicated that prostacyclin has beneficial hemodynamtc effects in primary puhnonary hypertension, both acutely {6-81 ~nd chronically (9,10}, and that a vasodilator response to prostacyclin predicts response to other vas~dilators ( I I , 1 2 ) , Ho~ever, all of these reports involved sn'all numbers of patients. We have studied the hamodynamlc effects of prostacyclin in a large group of primary pulmonary hypertension patients.
Materials and Methods Sixty-five patients with primary pulmonary hypertension ranging in age from one to sixty-five years were infused with prostacyclln. Stapwtse increases in prostacyclin infusion rate were made every 15 minutes until either I} pulmonary arterial pressure increased 30~. 2) systemic arterial pressure decreased 30~. or 3} adverse events dictated prostacyclin discontinuation. Measurements of heart rate, right atrial p~essure, mean pulmonary arterial pressure, mean systemto arterial pressure, pulmonary capillary wedge pressure (or loft atrial pressure}, cardiac output, and arterial pO~ were recorded at baseline and at each prostacyclln" dose. Pulmonary vascular resistance and systemic vascular resistance were calculated at baseline and at each prostaeyclin dosc~ Using repeated measl~res of variance (least squares method), the statistical significance of thc apparent relationship }between changes in prostacycltn dose and changes' in each variable was ~ested. Results Dose-related increases tn heart rate (p<.001) and cardiac output {p<.001), and dose-related decreases in mean pulmonary arterial pressure (p<.001), pulmonary vascular resistance (p<.O01}. mean systemic arterial pressure (p<.0Ol). and systemic vascular resistance (p<.001} occurred. Figure 1 depicts the relationship between prostacyclin dose and pulmonary vascular resistance in the 6b p~i,aary pulmonary hypertension studied.
F I G U R E 1: Effects of I n c r e a s i n g F L O L A N doses on pulmonary vascular resistance 130 re D. uJ z_ .J uJ m
u~ O ¢u tJ uJ rL
120 110 100 90 80.
70. 60 50 t
2
4
6
8
"
I I
,
~ ~
"
}
; I1 l
,
I ~
i I'llllI ]
,
i
10 12 D1 D2MAXP1 P2 I>3
FLOLAN DOSES(ng/kglmln)
Seven pat|eats were identified who increased pulmonary vascular roe!stance in response to prostacyclin • Discussion The present study probably constitutes the largest clinical experience with a single therapeutic agent in primary pulmonary hypertension ever reported. Prostacycltn had clearly beneficial hemodynamic effects tn the great majority, but not all, of the patients studied. These observations suggest that I) prostacyclin infusions are wall tolerated by primary pulmonary hypertension patients, 2) prostacychn can identify a subpopulation of prlr,;ary pulmonary hypertension patients who are unlikely to toted'ate or benefit Item oral vasodtlafurs, and 3) prostaeyelin could have a therapeutic role in s o m e primary pulmonary hypertension patients.
Reference~ I. Packer M: Vasodilator th~rapy for primary pulmonary ilypeften~ion: hmitations and hazards. Ann Int Mad 193:258-270, 1985 2. Rich S, Levy PS: Characteristics of surviving and nonsurvivlng patients with primary pulmonary hypertension. Am J Med 76:573-579, 1984 3. Buch J, Wennevold A: Hazards of diazoxide in pulmonary hypertension. Br Heart J 46:401-403, 1981 4. Fa~bar HW, Karlinsky J ~ , Faling LJ: Fatal outcome following nlfedipine fr~r primary pulmonary hypertension. Chest 83:708-70~, 1983 5. Packer M, bledina N, Yushak M: Adverse hemodynamic and clinical effects of calcium channel blockade in pulmonary hypertension secondary to
128
obltterative pulmonary vascular d i s e a s e . J Am Cell Cardtol 4:890-8910 1984 6. R u b i n LJ, G r o v e s BM. R e a v e s J T , at el: Prostacyclin-induced acute pulmm~ary vasodUation in primary pulmonary hypertension. Circulation fi6:334-338, 1982 7. Watktns WD, Peterson HB, Crone RK, et el: Prostacyclio and prostaglandin l~l for sever~ idiopathic pulmonary a r t e r y hypertension. Lancet 1:1083, 1980 8. Roskovec A. Mlnty K, Stradling J, at el: Value of acute vasodflator s t u d i e s in management of primary pulmonary hypertension. Circulation 68S:49, 1982 9. Ittgenbottam T, wells F, Wheeldon D, at at: Long terla treatment of primary pulmonary hypertension
ABSTRACTS with continuous intravenous epoprostenol (prostacycltn). Lancet 1:1046-~1047, 1984 1O. Jones DK, Higonbottam T, Wallwork J: Practical e x p e r i e n c e of long t e r m p r o s t a c y c l i n in p a t i e n t s with primary pulmonary hypertension. Am Roy Reap Dis 131:85A, 1985 11. B a r s t RJ, Hall JC, Stalcup SA: Response to prostacyclln predicts response to subsequent vasodtlatnr therapy In children and young adults with primary pulmonary h y p e r t e n s i o n . In Doyle EF, I~ngle MA, ~ . S p r i n g e r Verlag° New York, 1986, pp 952-953 12. G r o v e s BH, ftubin LJ, Froaolone HF, et al: A comparison of the acute hemodynamic effects of prostacyclln and hydralazlne in primary pulmonary hypertension. Am ileart J 11Q:1200-1204, 1985
ABSTRACTS
TITLE:
ACUTI~ IIEMODYNAMIC EFFECTS OF PROSTACYCLIN HYPERTENSION PATIENTS
IN 65 PRIMARY P U L H O N A R Y
AUTHORS;
W. Long. M.D., R. Barst, M.D., A. Flshman, M.D., B. Groves. M.D., M. Frosolono, Ph.D.. K. Moser, M.D., H. Palevsky. M.D., J. Reeves, M.D., L. Rubln, M.D., A. Cute, M.D., Ph.D.
AFFILIATION : Division of Clinical Research, Wellcome Re~,earch Laboratories, Research Triangle Park, North Carolina 27577
Primary pulmonary hypertension is a poorly understood disorder in which elevations in pulmonary vascular resistance lead to progressive right ventricular dysfunction, exorcise intolerance, syncope, and death. Interest in vasodilator therapy for primary pulmonary hypertension remains high; approximately one quarter of primary pulmonary hypertension patients appear to .benefit (1), It appears that primary pulmonary hypertension patients who ~espond to vasodilators with increased cardiac output and decreased pulmonary arterial pressures have a better prognosis (1,21, but whether the better prognosis is due to actual treatment with vasodllators is doubted by some investigators (2}. ~In any case, va.Qodilator therapy can be llazardous in primary pulmonary hypertension patients with fixed pulmonary vascular beds, both acutely {3-5) and chronically, Several reports have indicated that prostacyclin has beneficial hemodynamtc effects in primary puhnonary hypertension, both acutely {6-81 ~nd chronically (9,10}, and that a vasodilator response to prostacyclin predicts response to other vas~dilators ( I I , 1 2 ) , Ho~ever, all of these reports involved sn'all numbers of patients. We have studied the hamodynamlc effects of prostacyclin in a large group of primary pulmonary hypertension patients.
Materials and Methods Sixty-five patients with primary pulmonary hypertension ranging in age from one to sixty-five years were infused with prostacyclln. Stapwtse increases in prostacyclin infusion rate were made every 15 minutes until either I} pulmonary arterial pressure increased 30~. 2) systemic arterial pressure decreased 30~. or 3} adverse events dictated prostacyclin discontinuation. Measurements of heart rate, right atrial p~essure, mean pulmonary arterial pressure, mean systemto arterial pressure, pulmonary capillary wedge pressure (or loft atrial pressure}, cardiac output, and arterial pO~ were recorded at baseline and at each prostacyclln" dose. Pulmonary vascular resistance and systemic vascular resistance were calculated at baseline and at each prostaeyclin dosc~ Using repeated measl~res of variance (least squares method), the statistical significance of thc apparent relationship }between changes in prostacycltn dose and changes' in each variable was ~ested. Results Dose-related increases tn heart rate (p<.001) and cardiac output {p<.001), and dose-related decreases in mean pulmonary arterial pressure (p<.001), pulmonary vascular resistance (p<.O01}. mean systemic arterial pressure (p<.0Ol). and systemic vascular resistance (p<.001} occurred. Figure 1 depicts the relationship between prostacyclin dose and pulmonary vascular resistance in the 6b p~i,aary pulmonary hypertension studied.
F I G U R E 1: Effects of I n c r e a s i n g F L O L A N doses on pulmonary vascular resistance 130 re D. uJ z_ .J uJ m
u~ O ¢u tJ uJ rL
120 110 100 90 80.
70. 60 50 t
2
4
6
8
"
I I
,
~ ~
"
}
; I1 l
,
I ~
i I'llllI ]
,
i
10 12 D1 D2MAXP1 P2 I>3
FLOLAN DOSES(ng/kglmln)
Seven pat|eats were identified who increased pulmonary vascular roe!stance in response to prostacyclin • Discussion The present study probably constitutes the largest clinical experience with a single therapeutic agent in primary pulmonary hypertension ever reported. Prostacycltn had clearly beneficial hemodynamic effects tn the great majority, but not all, of the patients studied. These observations suggest that I) prostacyclin infusions are wall tolerated by primary pulmonary hypertension patients, 2) prostacychn can identify a subpopulation of prlr,;ary pulmonary hypertension patients who are unlikely to toted'ate or benefit Item oral vasodtlafurs, and 3) prostaeyelin could have a therapeutic role in s o m e primary pulmonary hypertension patients.
Reference~ I. Packer M: Vasodilator th~rapy for primary pulmonary ilypeften~ion: hmitations and hazards. Ann Int Mad 193:258-270, 1985 2. Rich S, Levy PS: Characteristics of surviving and nonsurvivlng patients with primary pulmonary hypertension. Am J Med 76:573-579, 1984 3. Buch J, Wennevold A: Hazards of diazoxide in pulmonary hypertension. Br Heart J 46:401-403, 1981 4. Fa~bar HW, Karlinsky J ~ , Faling LJ: Fatal outcome following nlfedipine fr~r primary pulmonary hypertension. Chest 83:708-70~, 1983 5. Packer M, bledina N, Yushak M: Adverse hemodynamic and clinical effects of calcium channel blockade in pulmonary hypertension secondary to
128
obltterative pulmonary vascular d i s e a s e . J Am Cell Cardtol 4:890-8910 1984 6. R u b i n LJ, G r o v e s BM. R e a v e s J T , at el: Prostacyclin-induced acute pulmm~ary vasodUation in primary pulmonary hypertension. Circulation fi6:334-338, 1982 7. Watktns WD, Peterson HB, Crone RK, et el: Prostacyclio and prostaglandin l~l for sever~ idiopathic pulmonary a r t e r y hypertension. Lancet 1:1083, 1980 8. Roskovec A. Mlnty K, Stradling J, at el: Value of acute vasodflator s t u d i e s in management of primary pulmonary hypertension. Circulation 68S:49, 1982 9. Ittgenbottam T, wells F, Wheeldon D, at at: Long terla treatment of primary pulmonary hypertension
ABSTRACTS with continuous intravenous epoprostenol (prostacycltn). Lancet 1:1046-~1047, 1984 1O. Jones DK, Higonbottam T, Wallwork J: Practical e x p e r i e n c e of long t e r m p r o s t a c y c l i n in p a t i e n t s with primary pulmonary hypertension. Am Roy Reap Dis 131:85A, 1985 11. B a r s t RJ, Hall JC, Stalcup SA: Response to prostacyclln predicts response to subsequent vasodtlatnr therapy In children and young adults with primary pulmonary h y p e r t e n s i o n . In Doyle EF, I~ngle MA, ~ . S p r i n g e r Verlag° New York, 1986, pp 952-953 12. G r o v e s BH, ftubin LJ, Froaolone HF, et al: A comparison of the acute hemodynamic effects of prostacyclln and hydralazlne in primary pulmonary hypertension. Am ileart J 11Q:1200-1204, 1985