Hemodynamic Effects of Nifedipine in Primary Pulmonary Hypertension

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1 174 JACC Vol 2, No I July CASE REPORTS Hemodynami Effets of Nifedipine in Primary Pulmonary Hypertension JOHN S, DOUGLAS, Jr., MD, FACC Atlanta, Georgia Progressive dyspnea and synope ourred in a young woman with primary pulmonary hypertension despite therapy with hydralazine. Abnormal pulmonary artery reativity was doumented by an additional inrease in pulmonary artery pressure and pulmonary vasular resistane during exerise and after an episode of hydralazine-indued hypotension. Nifedipine redued rest and exerise pulmonary artery pressure, pulmonary vasular resistane and right ventriular stroke work, and inreased ardia output and markedly improved exerise apaity. Reevaluation after 6 months showed persistene of the favorable hemodynami and linial effets. Vasodilator therapy, potentially hazardous beause of effets on systemi vasular resistane, an be evaluated safely only with hemodynami monitoring. Nifedipine may be a useful drug in seleted patients with primary pulmonary hypertension. Primary pulmonary hypertension is a rare disorder haraterized by progressive dyspnea, synope and right-sided heart failure, resulting in death within 3 to 5 years in the majority of patients (I), Although reognized as a linial entity over 30 years ago (2), the etiology and pathogenesis of this disease remain obsure, Wood (3) suggested that a pulmonary vasoonstritor fator was operative and others (4,5). as a result of pathologi studies, hypothesized that prolonged vasoonstrition of the pulmonary arteries of unknown ause is the primary pathophysiologi event. Subsequent development of medial hypertrophy of the musular pulmonary arteries and finally intimal fibrosis our. Symptoms are not speifi in this disorder and in many patients the diagnosis is made late in the ourse of the disease, Until reently, attempts at therapy had been disouraging. The most promising therapeuti effort in this disease has been the use of vasodilator agents. In ertain patients. presumably still in the early phases of the disease. vasodilators have proved effetive in reduing pulmonary artery resistane and. in many ases. ameliorating symptoms to a variable degree (6-13), In many patients, however. the redution in pulmonary vasular resistane was aompanied by an inrease in pulmonary blood flow but no derease in From th Departments of Mediine and Radiology. Emory Uruversuy Shool of Mediine. Woodruff Medial Center. Atlanta. Georgia. Manusript reeived Deember revised manusnpt reeived January aepted January 19, 1983 Addre s for repnnts: John S Douglas. Jr, MD, Cardiovasular Laboratory. Emory University Clini, 1365 Clifton Road N.E, Atlanta. Georgia (l 1983 by the Arnenan College of Cardiology pulmonary artery pressure. This ombination of high pulmonary blood flow and pressure is theoretially undesirable and the long-term effets on the right ventrile and pulmonary vasular bed are unknown. In addition. powerful vasodilating agents may signifi antly lower systemi arterial pressure and resistane with undesired onsequenes. Serious hypotensive reations and death have been reported with the use of vasodilator therapy in primary pulmonary hypertension (14-16). This report desribes a patient with primary pulmonary hypertension whose ondition worsened with hydralazine therapy and who experiened a hypotensive reation to this agent while under hemodynami observation. The hemodynami hanges and linial response with nifedipine are also reported. Case Report Clinial features. A 33 year old white woman was admitted to Emory University Hospital with a 10month history of progressive dyspnea on effort and three episodes of synope. Dyspnea was gradual in onset, ourring initially with vigorous biyle exerise; dyspnea subsequently ourred with walking at a moderate pae and limited the patient to limbing only one flight of stairs. Synope ourred during or after exertion. The patient had been otherwise healthy. did not smoke or use appetite-suppressing drugs and was free of known pulmonary disease. Beause of the progressive symptoms and findings of an enlarged main pulmonary /83/$3 DO

2 JACC Vol 2. No I DOUGLAS 175 artery on hest X-ray study, the patient was referred for ardia evaluation. On physial examination, the patient appeared healthy and had no dyspnea or yanosis at rest. Blood pressure was 115/72 mm Hg. Heart rate was 68 beats/min and regular. Jugular venous pressure and ontour were normal and arotid pulsations were normal. The hest was lear. The first heart sound was normal; the seond heart sound split widely on inspiration with an aentuated pulmonary omponent. An early systoli lik and soft early diastoli blowing murmur were heard along the left sternal border. There were no gallop sounds. Chest X-ray films showed normal heart size on the anteroposterior projetion and right ventriular prominene on the lateral projetion. The main pulmonary artery was enlarged. The peripheral pulmonary vasulature was normal, The eletroardiogram revealed normal sinus rhythm and right axis deviation. and the ehoardiogram showed a redued a dip of the pulmonary valve suggesting pulmonary hypertension. Arterial blood gases were normal at rest and pulmonary funtion studies were normal. The ventilationperfusion lung san was normal, Tests for antinulear antibody and rheumatoid fator were negative. Cardia atheterization revealed moderate pulmonary hypertension with normal pulmonary apillary wedge pressure: pulmonary artery pressure 51/20 (mean 32). right ventriular pressure 55/6, right atrial pressure 3 and pulmonary apillary wedge pressure 6 mm Hg. Oximetry revealed no intraardia shunts. Pulmonary angiography, left ventnulography and supravalvular aortography were normal. On the basis of these studies, a diagnosis of primary pulmonary hypertension was made. The patient was plaed on oumadin empirially and hydralazine therapy was begun at 10 mg four times a day and inreased to 50 mg four times a day over a 3 week period. Symptoms of dyspnea on effort ontinued to worsen over a 5 month period. with the development of mild dyspnea at rest and marked dyspnea on limbing less than half a flight of stairs. The patient experiened synope one after disiplining a hild and twie after effort, and was referred for reevaluation. Physial findings, eletroardiogram, hest X-ray films and blood gases were unhanged. Methods of hemodynami measurements. To measure hemodynami hanges with exerise and evaluate the response to vasodilator therapy, a Swan-Ganz atheter was plaed in the pulmonary artery and the left radial artery was annulated for diret blood pressure reording. Measurement of ardia output was performed by thermodilution (mean of three determinations). Derived hemodynami variables were alulated using the following formulas: PYR PA - PCW ----x 80 CO SYR RYSWI SA - RA ----x 80 CO SY(PA-RA) (0.0136) Body surfae area ' where PYR is pulmonary vasular resistane, PA is mean pulmonary artery pressure, PCW is mean pulmonary apillary wedge pressure, CO is ardia output, SA is mean systemi arterial pressure, RA is mean right atrial pressure, SY is stroke volume and RYSWI is right ventriular stroke work index. After reeiving no medianons for 2 weeks, the patient underwent pulmonary artery and systemi arterial pressure reordings and ardia output measurements while resting in the supine position. She was then exerised at 50 watts on an upnght biyle after the gauges were readjusted to atrial level, and the measurements of pressure and flow were repeated at frequent intervals during exerise. A biyle training session had been onduted the previous day. On day I. measurements of rest and exerise ardia output and pulmonary and systemi pressures were made before and after nifedipine. 10 mg orally. On day 2, these reordings were made before and sequentially for 9 hours after nifedipine, 20 mg orally. On day 3, reordings were made before and for 9 hours after nifedipine, 30 mg orally, and on day 4, the response to oral hydralazine was tested. After 6 months of nifedipine therapy, the patient was rehospitalized and repeat measurements of pulmonary artery pressure and flow were performed. Data were olleted at rest and during biyle exerise at 50 and 100 watts. The nifedipine dose shedule at that time was 10 mg orally every 2.5 hours for a total of 60 mg during the day and 20 mg at bedtime. Hemodynami measurements at rest were made hourly for 24 hours. Response to exerise was reorded 2 hours after the seond dose of the day. Hemodynami response to exerise and vasodilator therapy. Before treatment with nifedipine, pulmonary artery pressure at rest was moderately elevated (69/27 mm Hg, mean 47). This was an inrease of 50% from that reorded at atheterization 5 months previously. Pulmonary vasular resistane was elevated at rest to 654 dynes-s-m - 5 (normal = 67 ± 30). Systemi arterial pressure and ardia output were normal (Table I). With mild biyle exerise (50 watts), the patient beame dyspnei and fatigued easily, ompletmg only 4.5 minutes of exerise. During exerise, pulmonary artery pressure inreased sharply to 118/54 mm Hg (mean 76). Pulmonary vasular resistane, whih was markedly elevated at rest, inreased by 50% during exerise and the pulmonary vasular resistane/systemi vasular resistane ratio inreased to Cardia output inreased 20o/ and systemi vasular resistane dereased 11%. These

3 176 DOUGLAS JACC Vol 2. No 1 July Table 1. Hemodyn ami Data at Rest and During the Fifth Minute of Biyle Exerise Before and After Therapy With Nifedip ine 3h After Nifedipine After 6 Mo. Nifedipine (10 mg orally Control (20 mg orally) every 2.5 h) Rest 50 W Rest 50 W Rest 50 W 100 W PA pressure (mm Hg) Systoli Diastoli Mean SA pressure (mm Hg) Systoli Diastoli Mean Cardia output (liters/min) PVR SVR Heart rate (beats/min) Stroke volume (ml) PCW pressure (mm Hg) RA pressure (rnrn Hg) 2 I Arterial O2sat (%) Pa0 2(rnrn Hg) PVR/SVR RVSWI (gm/beat per m 2 ) PA = pulmonary artery; Pa0 2 = arterial oxygen pressure; PCW = pulmonary apillary wedge: PVR = pulmonaryvasular resistane (dynes-s-m- 5). RA = nght atrium; RVSWI = right ventriular stroke work index: SA = systemi artery: sat = saturation: SVR = systemi vasular resistane (dynes-s-m- 5). findin gs onfi rmed the presene of abnormal pulmonary vasular reativity. Vasoonstrition ourred, whereas the normal response to exerise is passive dilation of the pulmonary vasular bed. After administration ofnifedipine in doses of 10, 20 and 30 mg orally, a derease in mean pulmonary artery pressure at rest ourred to 43, 37 and 34 mm Hg, respetively, when measured 3 hours after ingestion. Pulmonary vasular resistane at rest was redued 36 to 44% by nifedipine in the preeding doses, while signifi ant inreases in exerise tolerane ourred with all doses. Flushing, onsidered unpleasant to the patient, was experiened with the 30 mg dose of nifedipine; 20 mg was the maximal dose that was well tolerated. Hemodynami responses to exerise before and 3 hours after 20 mg of nifedipine are reported in Table I. (Data reorded at I and 2 hours after ingestion were inomplete beause of tehnial fators, but pulmonary artery pressure and ardia output were quite similar to those reorded at 3 hours after ingestion.) Nifedipine blunted the pulmonary vasoonstritive response noted with exerise and produed a greater pulmonary blood flow at redued pulmonary artery pressure. Cardia output rose to 8.5 liters/ min during biyle exerise at 50 watts. This exerise level was aomplished at a mean pulmonary artery pressure of 50 mm Hg ompared with an exerise pulmonary artery pressure of 76 mm Hg before nifedipine. Whereas pulmonary vasular resistane at rest had been 654 dynes-s-m :" before nifedipine and inreased by more than 50% with exerise, pulmonary vasular resistane after nifedipine dereased to 335 dynes-s-m- 5 at rest and inreased only 25% during exerise at 50 watts. Three hours after ingestion of nifedipine, 20 mg, the patient ould exerise for 30 minutes at 50 watts ompared with an exerise tolerane of less than 5 minutes before treatment. Nine hours after ingestion of nifedipine, 20 mg, exerise tolerane was redued to less than 5 minutes at 50 watts. Figure I shows the hemodynami measurements performed during the biyle exerise (50 watts) before and after three different doses ofnifedipine. Beause symptoms were experiened primarily during exerise, the therapeuti effet of greatest interest is that on exerise hemodynamis. A signifiant therapeuti effet ourred after the 10 mg dose and a greater effet ourred after the 20 mg dose. At 3 hours after 20 mg of nifedipine, there was a 33% derease in exerise pulmonary artery pressure. This effet appeared to be waning at 7 hours and was gone by 9 hours after oral ingestion. With the 30 mg dose, the magnitude of hange at 3 hours was omparable with that of the 20 mg dose. At 9 hours after the 30 mg dose, a mild vasodilator effet persisted, as evidened by lower pulmonary artery pressure and resistane and higher ardia output ompared with pretreatment levels. Figure 2 depits hanges in hemodynamis at rest that ourred after oral administration of two 25 mg doses of hydralazine. After the initial dose, there was a derease in pulmonary artery pressure from 75/42 to 60/25 mm Hg, an

4 '). After JACC Vol 2. No 1 DOUGLAS 177 Figure 1. Hemodynami measurements dunng exo erise before and after nifedipme. 10, 20 and 30 ;:> 1000 Q! 109orally. Data were olleted dunng the fifth min- ute of biyle exerise (5att,) CO = ardia output; N = nifedipine; PA = mean pulmonary <, artery pressure; PAS = pulmonary artery systoli pressure; PYR = pulmonary vasular resistane. > N 10mg N 20mg N JOmg Q! l M PAS ::J 100 PVR n: '», Q! a: E ::J >- o --' ro :; E :; CO ::J (L o E :; " I! ) 0 0 '2 inrease in ardia output from 5 to 5.4 liters/min and a small derease in pulmonary vasular resistane. One hour after the seond dose of hydralazine, the patient was allowed to sit up to urinate. At that point, she beame nauseated, presynopal and developed tahyardia. Blood pressure dereased to 50 mm Hg systoli; it returned to pretreatment levels when the patient was allowed to resume a supine posture and the feet were elevated. Subsequently. pulmonary artery pressure inreased signifiantly to 99/43 mm Hg and hest disomfort ourred. Marked inrease In pulmonary vasular resistane was noted (533 to 886 dynes-sm r a period of observation during whih pulmonary vasular resistane remained stable. sublingual nifedipine, 10 rng, was administered. The hest disomfort promptly dissipated and there was a signifiant and abrupt derease in pulmonary artery pressure ( 100/38 to 60/26 mm Hg). Cardia output inreased and a 60% derease in pulmonary vasular resistane ourred. On outpatient therapy. exerise tolerane improved dramatially on nifedipine, 20 mg orally 4 times a day. An improved quality of life resulted as ativity levels returned to near normal. Beause of Hushing with a 20 mg dose of nifedipine, the dosing shedule was adjusted to 10 mg orally every 2 Y2 hours for a total of 60 mg during waking hours and 20 mg at bedtime. After 6 months of therapy, pulmonary artery pressure and How were measured again (Table I). Mean pulmonary artery pressure and pulmonary vasular resistane at rest were omparable with levels reorded 3 hours after 20 mg of nifedipine orally during the evaluation, 6 months previously. During 24 hours of observation, mean pulmonary artery pressures and resistane at rest were virtually onstant on the frequent dosing shedule. However, during biyle exerise at 50 watts, mean pulmonary artery pressure inreased only to 39 mm Hg as ompared with 76 mm Hg before any therapy and 50 mm Hg after 20 mg of nifedipine. Pulmonary vasular resistane, whih had inreased dramatially before treatment, dereased slightly at 50 watts and dereased further at 100 watts (Fig. 3). At 100 watts of biyle exerise, whih ould be maintained easily for 30 minutes, ardia output rose to 10.5 liters/min and the mean pulmonary artery pressure was 44 mm Hg. (L, o Time (hours) Disussion Sine the imtial haraterization of primary pulmonary hypertension as a linial entity by Dresdale et al. (2), attention has been foused inreasingly on pulmonary arteriolar onstrition as an important or primary pathophysiologi fator in this rare disorder. Early workers (2,3) observed transient redutions in pulmonary artery pressure and resistane with injetions of vasodilator agents suh as aetylholine and tolazoline. leading to a searh for an effetive therapeuti agent. Subsequently, long-term benefit was reported in a small number of patients with phentolamine (7), diazoxide (9). isoproterenol (6) and hydralazine (8), Figure 2. Hemodynami hanges after two doses of hydralazin orally (po) Systemi hypotension and presynope ourrd when the head was elevated. Chest disomfort ourred in assoiation with inreased pulmonary artery pressure and pulmonary vasular resistane. and promptly abated after nifedipine sublmgually (sl). >- Q! () '" 3 tl u E '!! - ::J> Q! a. a: t loot 50 o f t:!ydralazme 25mg po l 25mg po l o Time (Hours)

5 17 8 DOUGLAS JACC Vol 2. No I 140 Pn or to Nlfed lpm e Afte r 6 month s on Nlfe dlpme Q) 1200 l'? 120 u ::> VI " '",, VI <ii 1000 Q) 100 iii n: Q) -, ::>.0: :R () o.>, 15 VI II> ;;; _0. > '" >- 0 COl PA 10 ;;; 3 o - 0 ::> 0, 20 3 " E 200 CO"'--" 5 U "3 :=. o, 0 0 Re sl 50 Rb i WailS WailS wa us Figure 3. Comparison of rest andexerise pulmonary artery pressure, resistane and flow before nifedipine and after 6 months of therapy. Nifedipine, 10 mg orally, was administered 2 hours and 4.5 hours before therestandexerisemeasurements at the6 month evaluation. Data were reorded during the fifth minute of exerise. Abbreviations as in Figure I. but eah agent had disadvantages or limited effetiveness, or both. Hydralazine has been the most widely applied vasodilator sine Rubin and Peter (8) reported redutions in pulmonary arteriolar resistane, inreased ardia output and symptomati improvement in four patients with primary pulmonary hypertension. However, this agent has not been shown to lower pulmonary artery pressure. Therefore, by inreasing pulmonary blood flow without reduing pulmonary artery pressure, hydralazine imposes an additional burden on the right ventrile, and long-term effets of inreased flow and pressure on the pulmonary vasular bed are assumed to be undesirable. In addition, adverse hemodynami reations and death were reported (15,16) with the use of hydralazine in primary pulmonary hypertension. Reent preliminary reports ( II, 17) indiate effetive pulmonary arteriolar dilation an be ahieved with alium bloking agents. These agents, by inhibiting slow-inward alium movement in vasular smooth musle, have been shown to impede exitationontration oupling produing relaxation of vasular smooth musle. Effets of nifedip ine. Our study patient had experiened progressive exerise limitation and her pulmonary artery pressure had inreased sine the initial evaluation only 5 months previously. Hydralazine was of no symptomati benefit and its use produed an episode of signifi ant systemi arterial hypotension aompanied by hest disomfort, redued ardia output and inreased pulmonary vasular resistane. This type of pulmonary vasospasti response to sympatheti stimulation has been previously desribed in a patient with primary pulmonary hypertension (18). Pulmonary vasular tone in our patient was inreased at rest and was influened by physial ativity. Pulmonary artery pressure and pulmonary vasular resistane inreased by more than 50% with light biyle exerise, and exerise tolerane was markedly restrited. This response is similar to that reported by Ruskin and Hutter (7 ) in a patient who had pulmonary vasoonstrition at rest that inreased with exerise. Nifedipine had benefiial effets on rest and exerise hemodynamis in our patient when tested aute ly and these effets were present on reevaluation 6 months later. This favorable long-term effet is signifiant in view of the tahyphylaxis reported with some vasodilators. Cardia output inreased with nifedipine, leading to improved tissue oxygenation and exerise tolerane. The inrease in pulmonary vasular resistane noted during exerise before treatment with nifedipine was diminished by aute administration of nifedipine and, after 6 months of therapy, pulmonary vasular resistane dereased during exerise. Although the resistane in both systemi and pulmonary iruits was redued by nifedipine, a redution in the ratio of pulmonary to systemi vasular resistane indiates greater pharmaologi responsiveness in the pulmonary irulation. Rest and exerise pulmonary artery pressures were redued by nifedipine. Although Rubin et al. (19) have shown that the failing right ventrile might benefit from a vasodilator that does not redue pulmonary artery pressure, the long-term impat of an inreased pulmonary artery blood flow at persisting high pulmonary artery pressure remains to be determined, but will probably be negative. Meha nism of nifedipine's effets. Of partiular interest was the abilityof nifedipineto reverse thepulmonaryvasoonstrition that ourred after hydralazine-indued systemi arterial hypotension and was presumably mediated by irulating ateholamines. The apaity to blok ateholamine-indued vasoonstrition was one of the earliest observations made of the effets of alium antagonists on vasular smooth musle (20). The inrease in ardia output experiened with nifedipine at rest and during exerise does not appear to be due to opening of intrapulmonary shunts beause no hange in arterial oxygen tension ourred. The fator limiting ardia output appeared to be high pulmonary vasular resistane. Inreasing ardia output with nifedipine is believed to be due to a diret effet on pulmonary arterial smooth musle, produing vasodilation, redued right ventriular afterload, redued right ventriular work and inreased pulmonary and systemi blood flow. The net result in our patient was greatly improved exerise tolerane. Prediting the response to vasodilator therapy. The suess of vasodilator therapy in primary pulmonary hypertension is dependent on the tone present in the pulmonary vasular bed, the responsiveness of the pulmonary arterioles to the vasodilating agent and the magnitude of fixed pathologi hanges. As suggested by Ruskin and Hutter (7), the relative lability of the pulmonary artery pressure and resistane may serve as a useful marker for prediting the response to vasodilator therapy. Patients with long-standing,

6 JACC Vol 2. No DOUGLAS 179 severe, fixed pathologi hanges would be expeted to benefit less from vasodilator therapy than would patients with vasoonstrition and little pathologi hange. Our experiene with this patient suggests that nifedipine may be a useful drug in treating patients with primary pulmonary hypertension in whom pharmaologially responsive vasoonstrition is doumented. Referenes I. Gupta BD. Moodie DS. Hodgman JR Pnrnary pulmonary hyperten- 14,IOn in adults. Clv Clin 1980: Drsdal DT. Shultz M. Mihtom RJ. Primary pulmonary hyperten- 15. sion Am J Md Wood P. Pulmonary hypertension WIth speial referene to the vasoonstritive fator. Br Heart J 1958;20' Wagnvoort CA. Wagenvoort N. Primary pulmonary hypertension: a pathologi study of the lung vessels In 156 hrually diagnosed ases Cirulation 1970:42: Edward, WD. Edwards JE Cluneal primarypulmonary hypertension. Three pathologi types, Cirulation : Shetngar UR. Hultgren HN. Speter M. Martin R. Davres DII PrI' mary pulmonary hypertension: favorable effet of isoproterenol N Engl J Md 1976: Ruskin IN. Hutter AM Jr Primary pulmonary hypertension treated WIth oral phentolamine. Ann Intern Med 1979: Rubin LJ. Peter RH Oral hydralazine for primary pulmonary hypertension. N Engl J Md 1980, Honey M. Cotter L. Davies N. DI>on D. Chrual and hamodynarru effets of diazoxide In primary pulmonary hypertension. Thorax Horowitz JD. Brennan JB. Ohver LE. Harding D. Goble AJ. Louis WJ Effet.. of aptopnl (SQ ) In a pauent with primary pulmonary hypertension Postgrad Med J I I Carnnm F. Alberti E. Klugmann S. SalVI A Primary pulmonary hypertension effets of mfedipme Br Heart J 1980:44: Ml.eod AA. Wise JR Jr. Daly K. Jewitt DE Nrfedipme m primary and -eondarypulmonaryhypertension (abstr) Cirulanon 1981 :64(suppl IV) IV MoluuddmSM. Evtrbrook- D. Saenz A. et al. Hemodynami tftv of mtdipm In severe primary pulmonary hypertension (ubstr). Chest Buh J. Wennevold A. Hazards 01 drazoxide In pulmonary hypertn 'Ion Br Heart J 1981:46' Paker M. Greenberg B, Massie B. Dash H. Deleterious effets of hydralazme m patients with pulmonary hypertension. N Engl J Md 1982; Kronzon I. Cohen M. Winer HE Adverse effets 01 hvdrulazme In patients with primary pulmonary hyprten-ron JAMA Kumbara H. FUjimoto K. Wakabayaslu A. Kawai C Primary pulmonary hypertension. benefiial therapy 01 drluazm Am Heart J 1981:\0 \ Gorlm R. Clare FH. Zuska JJ. EVidene lor pulmonary vavoonstnnon In man Br Heart J 1958:20' Rubin LJ. Handel F. Peter RH. The efletv of oral hydralazine on right ventriular nd-diastuh pressure In patients with right ventriular tailure Cirulauon Godframd T. Kaba A. The role of alium In the ations of drug, on vasular vrnooth musle Arh Int Pharrnoodvn Ther I96(<'uppll