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Perfusion Matching in Primary Pulmonary Hypertension
Effects of Nifedipine on Ventilationl Perfusion Matching in Primary Pulmonary Hypertension* Christian Melot, M.D.; Robert Naeije, M.D.; Pierre Mola, M.D.; ]ean-Luc Vandenbo88che, M.D.; and Henri Denolin, M.D., Ph.D.
'Ibe effects of nifedipine on hemodynamics and pulmonary gas exchange were investigated in two patients with primary pulmonary hypertension. After 10 mg of the drug taken sublinguaDy, pulmonary and systemic vascular resistances decreased, cardiac output increased, and blood oxygenation was improved. As assessed by the multiple inert gas elimination technique, oifedipine induced a deterioration in
increased perfusion of units with low WQ. In spite of this negative effect on gas exchange, arterial Po. increased as a consequence ofincreased mixed venous Po. in relation to an aagmented cardiac output, and in one patient there was a decrease in the secondary atrial shunt. Both patients were clinically improved by the nifedipine as a long-term treatment.
with primary pulmonary hypertension have widened alveolar-arterial POI gradients and may become hypoxemic in advanced stages of the disease, when cardiac output also falls. l Studies using the multiple inert gas elimination technique have provided a better understanding of the mechanisms of abnormal gas exchange in these patients, and show in particular that a pharmacologic reduction in pulmonary vascular tone deteriorates ventilation/perfusion (VAlQ) matching.1,3 This potentially deleterious effect of pulmonary vasodilation received little attention in most of the recent reports on vasodilator therapy in primary pulmonary hypertension. 4-13 On the other hand, vasodilators tested until now in primary pulmonary hypertension with variable success are not specific fur the pulmonary circulation and have also been occasionally associated with serious adverse effects. l().13 We observed favorable clinical results in two patients with primary pulmonary hypertension who were given nifedipine and have investigated the effects of this drug on hemodynamics as well as on pulmonary gas exchange.
admission, a right heart catheterization showed severe pulmonary hypertension, partially reversible after a prostaglandin E 1 (PGEJ infusion, 0.02 ....g/kg/min (1llble 1). Hydralazine, 50 mg given fOur times per day orally, did not affect the gradient between pulmonary artery pressures and wedge pressures, but induced a 45 percent reduction in pulmonary vascular resistances, and was therefOre attempted as a long-term treatment. The patient, howeveJ; soon discontinued use ofhydralazine because of side effects consisting c1 malaise, headache, nervousness, and frequent nausea. PhYSical examination on admission showed her to be healthy-looking, slightly cyanotic, with no distress at rest, 157 em tall and weighing 60 kg. Blood pressure was !WOO mm Hg, heart rate 68 beatslmin, rectal temperature 36.SO C, and respiratory rate 16 breaths/min. There was jugular distension with visible A waves. The
ventilation/perfusion (VAJQ) relationships consisting in an
~ents
CASE REPORTS CASE
I
A 61-yeaJ'oOld woman was adpUtted with a history of progressively severe exertional dyspnea and fatigue over the preceding ten years. She denied previous use of drugs and had never before had symptoms suggestive of cardiac or pulmonary disease. From three years befOre admission, exertional dyspnea had become invalidating (walking on level ground) and was accompanied by chest pain and palpitations and on four occasions by syncope. One year before *From the Medical Intensive Care Unit and the Department of Cardiology, Saint-Pierre University Hospital, BrusselS, Belgium ManUscript received May 10; revision accepted August 23. Reprint requests: Dr. Melot, St-Pierre Unicersity HoB'pital, Rue Haute 322, B-1000 Brussels, Belgium
lungs were clear. The heart had apalpable 5. and aparasternal heave.
A grade 2 pansystolic murmUJ; increased at inspiration, was heard along the left: stemal border. The second heart sound bad a loudly accentuated pulmonic component. There was no hepatomegaly, ascites, or peripheral edema. An ECG revealed a right axis deviation and a right ventricular hypertrophy. Chest roentgenogram showed enlarged pulmonary arteries, with attenuation of the peripheral vascular markings and an enlargement of the right ventricle. Results of plasma electrolyte and renal and liver function tests, complete blood count, and a coagulation profile were normal. There was no laboratory evidence of connective tissue disorder. A ventilation! perfusion lung scan showed no evidence of pulmonary thromboembolic disease. A pulmonary arteriogram disclosed DO 6lling defect in the pulmonary vasculature. Lung function tests were normal, except for a reduction in diffusion capacity for carbon monoxide at 12.9 mJI minlmm Hg. M mode and two-dimensional _ b y showed a normal-sized left ventricle, a dilated right ventricle with marked hypertrophy of ventricular walls, and a normal aortic and
mitral valves. Aprominent Bpoint was noted on the bicuspid valve,
the pulmonic valve E-F slope was reduced, and the A wave was absent; the pulmonic valve showed a midsystolic notch, forming a "we' pattem. Contrast echocardiography was performed using intravenous (IV) injection of 5 percent dextrose in water and demonstrated a right-to-Ieft atrial shunt. Right heart catheterization was perfOrmed according to a procedure reported elsewhere. " Hemodynamic and gasometric measurements were obtained in duplicate befOre and 60 minutes after nifedipine, 20 mg given sublingually. As shown in 18ble 1, the basal determinations were comparable to those one year befOre (except for an increase in right atrial pressures), indicating slow progression
m
CHEST I 83 I 2 I February, 1883
203
Table I-MetJft Valua ofDuplictJte HernotIr/ntJmk and Blood GGaa DetennintJdona in noo Patienta WIlla PritntJ'lI PulmontJrrI H~
can PeEn HydrtJlszine, and Nifediptne
Patient 1, 1st Catheterization
Patient 2,
2nd Catheterization
Patient 2
Baseline PGEI Hydralazine Baseline Nifedipine Baseline Nifedipine Normal Umits*
Variable Arterial pH Arterial Po., mm Hg Arterial Peo., mm Hg Mixed Venous Po., mm Hg O.lhmsport, mllminlml 0. Consumption mlIminlml P(A-a) 0" mm Hg· Venous admixture, (If,)t Cardiac index, Uminlm' Heart rate, beat/min Mean arterial pressure, mm Hg Systemic vascular resistance, dyne.s.em- 5 Mean right atrial pressure, mm Hg Mean pulmonary artery pressure, mm Hg Pulmonary artery wedge pressure, mm Hg Pulmonary vascular resistance, dyne.s.em- 5
7.46 46 27 27 292 125 70 34 1.9 75 76 1753 9 74 8 1756
7.45 56 29 35
7.46
63
25 37 568 136 56 22 3.3 92 75 1018 8 72
465 131 58 28 2.8 74 70 1140 7 53 8 787
9
963
7.48 42 26 25 320 133
77 34 2.0 75 78 1656 13 75
7
1733
7.48 49 27 30 470 147
69
29 2.8 95 58
SOl 14 62
8
1002
7.51 81 25 31 382 133 42 8 2.1 82 95 1828 7 53
5
992
7.55 85 22 37 615 130 41 10 3.4 116 82 1020 4 54
5 641
7.38 - 7.44 SO - 102 32 - 42 34 - 481 450 - 850 100 - 200 0-20 0.1 - 10 2.6 - 4.6 50 - 100 70 - 105 650 - 1350 1-9 8 - 20
5 -14
25 - 100
·Calculated using the ideal alveolar gas equation, assuming a respiratory ratio equal to 0.8. tCalculated as (capillary 0. content-arterial 0, content/capillary 0. content-mixed venous 0. content). *Ranges obtained from right heart catheterizations performed in 23 healthy volunteen.
eX the disease. Nifedipine induced pulmonary vasodilation, increases in cardiac index and 0. transport, and improvement in blood oxygenation. Between the two baseline and the two nifedipine measurements, arterial and mixed venous blood and mixed expired gas were sampled to determine VAlQ distributions by the multiple
•
1.0 LIMIN
~
'.02
c
0 0
~ 0
~: 12,.
N.R.9 .1 .FORE NIFIDlPI. .
0
0.5
z
, . me. lured
I
42
"predicted 141
mmHg
SHUNT
1•
was distributed to a mode around the units with a VAlQ ratio of 2.6.
VENTILATION ....
20~
0
~
c
-'
~ Z
~ 0
•
BLOOD FLOW,
,
0
i
i
0.01 0.1 1.0 VENTILATION· PERFUSION
;
i
100.0
10.0 RATIO
1.0 LIMIN V
~: 11~
N. R. 9.1 AFTER NIFEDIPI.
0 -' II.
'.02
0
0 0
iii
~
me.lured: 4.
"
predict ed I 48
mmHg
VENTILATION - .
.. 0.5 0
!
SHUNT
-'
•
1
~
c
~
z ~
10~
BLOOD FLOW"
The shape and position of this mode along the VAlQ axis were comparable to those eX normal subjects." There was an additional mode ofblood flow to units with low VAlQ ratios (11.9 percent of total blood flow to units with VAlQ<0.2). Dead space was normal (32 percent of tidal volume)... Shunt was 20 percent of total blood flow. It must be noted that the inert gas method does not allow differentiation between pulmonary and cardiac right-to-left shunt. After nifedipine, there was a deterioration in VAlQ relationships, with an increased perfusion to units with low VAlQ ratios (18.9 percent eX total blood flow to units with VAlQ<0.2). Shunt decreased to 10 percent. Dead space increased to 51 percent, probably in relation to the reduction in pulmonary pressure. II Before as well as after nifedipine, the absence of diffusion abnormality was conBrmed by the good agreement between measured and predicted arterial POI' After nine months eX treatment ~th nifedipine, 20 mg orally four times a day, the patient felt much better and enjoyed a nearly normal life. Her exertional dyspnea markedly decreased, and she had no chest pain and no syncope. She wu even able to dance again-her favorite pastime, which she had had to abandon eight yean previously. CASE 2
0 0
1.0 0.01 0.1 VENTILATION· PeRFUSION
10.0 RATIO
100.0
FIGURE 1. VAlQ distributions before and after nifedipine, 20 mg sublingually, in patient 1.
204
inert gas elimination technique as described by Wagner and coworken. J5.JI The least-squares analysis with enfOrced smoothing was used to minimize the effects of random experimental enor. 17 the VAlQ distributions were combined with the mixed venous blood gases, cardiac output, minute ventilation, and P50 in a lung model described by West and Wagner' to predict the arterial pressure eX oxygen assuming complete alveolar-end capillary equilibrium in each lung unit. Minute ventilation and respiratory rate were measured using a pneumotachograph eX the Fleisch type connected with an electronic integrator (AUPREM 91 A). ]I the VAlQ distributions before and after nifedipine are shown in Figure 1. Before nifedipine, the majority of pulmonary blood flow
This 38-YeaN»ld woman had been in good health until one year previously, when she had several syncopes at exertion. ThereafteJ; she stdJered from progressively severe exertional dyspnea, fatigue, - frequent palpitations, and an average eX one syncope at exertion EtrecII ~ NlfedlpIne on VentlI8IIonIPerfuIIo (Mel« et II)
every 15 days. Three months before admission, she bad an episode eX congestive heart failure and received treatment consisting mrest, diuretics, and digitalis. She denied previous use of drugs. Physical examination showed her to be healthy, eupneic, and noncyanotic, 168 em tall and weighing 71 kg. Blood pressure was 120180 DlDl Hg, heart rate 80 beatslmin, rectal temperature 36.SO C, and respiratory rate 16 breaths/min. Heart auscultation showed a markedly accentuated second heart sound and a grade 2 pansystolic murmur along the left sternal border. The remainder eX the examination was unremarbble. An ECG revealed a right axis deviation and a right venbicular hypertrophy. Chest roentgenogram showed enlarged pulmonary arteries, with attenuation of peripheral vascular markings and enlargement of the right venbicle. Results of plasma electrolyte and renal and liver function tests, complete blood count, and coagulation pro61e were normal. There was no laboratory evidence of connective
•o
increased, while mixed venous blood oxygenation returned to within
normal limits. The VAlQ distributions in patient 2 before and after nifedipine were determined according to the same study protocol as in patient 1 (Fig 2). Before nifedipine administration, the majority ofblood flow was disbibuted to a mode around the units with WQ ratio of I. 7, and there was an additional mode of blood flow to units with low WQ ratios (3.9 percel)t of total blood flow to units with WQ<0.2). Dead space was normal, at 37 percent of tidal volume. The shunt was negligible (0.7 percent of total blood flow). After nifedipine administration, the perfusion of units with low VAlQ ratios was increased (to 9.4 percent of total blood flow to units with VAlQ
Dantzker and Bower have recently shown by the multiple inert gas elimination technique that VAl¢. relationships in patients with chronic obliterative pulmonary vascular disease (idiopathic or secondary to recUJTent pulmonary emboli) are only minimally abnormal, with a mean of 10 percent of cardiac output perfusing units with low VAI¢.. The same authors demonstrated that in such patients reduction of pulmonary vascular tone by an infusion of nitroprusside or
LIIiIN
"me.lured ••1 '.02 'predicted. mmHI 11
~
o
o II ;
~: 37,.
e.G. 9 31 .'OM NI'EDIPI. .
Q
0.5 VENTILATION .-.
Z
o
t=
c
~
t=
SHUNT
z
~
o
1
,
.0.7~ ~R58I""~",MIf1"
0.~1
o
ci.1 1:0 V!NTllATION • PERFUSION
10.0 RATIO
1.0 LIIiIN
tissue disorder. Ventilation/perfusion lung scan and pulmonary
arteriogram showed no evidence of pulmonary thromboembolic disease. Lung function tests were normal, excepted fOr a reduction in the diffusion capacity fOr carbon monoxide at 17.8 mlImin1mm Hg. M-mode and two-dimensional echocardiography showed a normalsized left ventricle, normal aortic and mitral valves, and a markedly dilated right venbicle. The pulmonic valve E-F slope was reduced, and the A wave was almost absent; a midsystolic notch was apparent. Contrast echocardiography disclosed no atrial or ventricular rightto-Ieft shunt. Right heart catheterization (18ble 1) showed marked pulmonary hypertension, normal 6lling pressures of the heart, and a 10\;Vered cardiac output. Arterial Po. was normal in the presence of marked alveolar hyperventilation and respiratory alkalosis. The 0. transport and mixed venous Po. were lmv. Administration of nifedipine, 20 mg sublingually, did not change pulmonary artery pressures, but increased cardiac output and 0. transport, while pulmonary vascular resistances were reduced by 33 percent. Arterial oxygenation
\0
C.G. 9 38 unR NIF!D. . . .
"" me.lured • IS '.02....... mmHg predicted. 14
Q
o
o
iii
.. o.s
o
~
t=
c~
BLOOD FLOW'-'
t=z
SHUNT
1&1
>
o
1
.0
o
FIGURE
0.01 0.1 1.0 VENTilATION· PERFUSION
10.0 RA'TIO
100.0
2. VAlQ distributions befOre and after nifedipine, 20
mg sublinguaUy, in patient 2.
isoproterenol deteriorates gas exchange without nega-
tive effect on arterial oxygenation, because mixed
venous POI is increased as a consequence of increased cardiac output. 3 Our observations are in agreement with these studies. We manipulated the lung model used to predict arterial PoI J8 and quantified the nifedipine-induced changes (Uble 2). It is apparent that negative effects on gas exchange by pulmonary vasodilation were slightly overcompensated by positive effects of increased cardiac output (and reduction of atrial right-to-Ieft shunt in patient 1). Crevey et alII observed no modiJication in VAl¢. relationships in 6ve patients with pulmonary hypertension (which was primary in four of them) after diltiazem administration, but this was probably due to the absence of physiologi-
cally relevant hemodynamic changes. Table !-TIaeoreticGl EJfecta rfN~-inducetl
eMng. on A.rwritJl Po. in &0 PadenII Wtda PritntJ,." PulrnontJ'lI H"".,.,..,.
\Baseline Arterial PO.
Patient 1
Patient 2 41 mm Hg 81 mm Hg
Nifedipine-induced changes -3 mm Hg-13 mm Hg VAlQ deterioration Shunt decrease +4mmHg 0 Mixed venous Po. increase due to cardiac output increase +6 mm Hg+ 18 mm Hg 48 mm Hg 84 mm Hg Resulting arterial Po. CHEST I 83 121 February, 1183
201
Calcium channel-blocking agents can influence cardiovascular hemodynamics by a complex interplay of systemic arterial vasodilation, a negative inotropic effect, and reflex phenomena. Among these drugs available for clinical use, nifedipine has been shown to be the most potent when administered in equal doses by weight to isolated tissue preparations. 13 In vivo, marked systemic vasodilation by nifedipine elicits a padrenergic response that accounts for an increase in cardiac output and an acceleration in heart rate, as observed in our patients. Pulmonary vasoconstriction is dependent on the availability of calcium to the effector cells, i4 and calcium channel-blockers have thus also been tried to induce pulmonary vasodilation in patients with primary or secondary pulmonary hypertension. A well-tolerated reduction in pulmonary vascular tone by nifedipine has been reported by Simonneau et allll in patients with decompensated chronic obstructive pulmonary disease, and by Camerini et aI18 in one patient with primary pulmonary hypertension. Verapamil was less effective in the study by Landmark et alIT in 12 patients with pulmonary hypertension (which was primary in nine of them). Pulmonary artery pressures decreased as a consequence of decreased cardiac output, and pulmonary vascular resistances remained unchanged. In the patients ofCrevey et al,2I diltiazem induced at rest only a slight decrease in pulmonary artery pressures, without change in cardiac output or in pulmonary vascular resistances. Kambara et alJ8 reported a marked pulmonary vasodilation by diltiazem in a younger patient. Thus, the available data on a limited number of patients suggest that nifedipine, and diltiazem to a lesser degree, may present an interesting effectiveness/toxicity ratio in the treatment of primary pulmonary hypertension. PGE. has been effective in reducing pulmonary hypertension, without side effects or excessive systemic vasodilation, in patients with decompensated chronic obstructive pulmonary disease·" and in one patient with primary pulmonary hypertension. J9 In our patient 1, PGE. appeared to be a more active pulmonary vasodilator than hydralazine. PGE. is regrettably not available for oral use, but may be helpful at right heart catheterization to determine the functional part of pulmonary hypertension. How did nifedipine treatment improve the clinical state in our patients? Their absolute level ofpulmonary artery pressures decreased moderately (17 percent in patient 1) or did not change at all (patient 2), but cardiac output increased in both. Limitation of cardiac output because of obstruction to flow through the lungs is likely to account at least in part for exertional dyspnea, syncope, and sudden death in advanced primary pulmonary hypertension.· In this respect, a pharmacologic increase in cardiac output, even without fall 208
in pulmonary artery pressures, may be the main
hemodynamic event leading to symptomatic improvement. 1 Another tentative explanation for the reduction in dyspnea in our patients might be a vagolytic effect of nifedipine that would reduce the afferent discharges from intrapulmonary mechanoreceptors. 3O•31 REFERENCES
n:
1 Voelkel N, Reeves Primary pulmonary hypertension. In: Moser ~M, edt Pulmonary vascular disease. New York: Marcel Dekker, 1979; 573-628 2 DantzkerDR, BowerJS. Mechanisms of gas exchangeabnonnality in patients with chronic obliterative pulmonary vascular disease. J Clin Invest 1979; 64:1050-55 3 Dantzker DR, Bower JS. Pulmonary vascular tone improves VAl Q matching in obliterative pulmonary hypertension. J Appl Physioll981; 51:607-13 4 Reeves fI: Hope in primary pulmonary hypertension. N Eng! J Med 1980; 302:112-13 5 Ellcayam U. Vasodilator therapy in primary pulmonary hypertension. Chest 1981; 79:253-54 6 Rubin LJ, Peter RH. Oral hydralazine therapy for primary pulmonary hypertension. N Eng} J Med 1980; 302:69-73 7 Ruskin IN, Hutter AM. Primary pulmonary hypertension treated with oral phentolamine. Ann Intern Med 1979; 90:772-74 Kelly DB. Isoproterenol as a potential 8 Daoud FS, Reeves pulmonary vasodilator in primary pulmonary hypertension. Am J Cardioll978; 42:817-22 9 Klinke W~ Gilbert JAL. Diazoxide in primary pulmonary hypertension. N Eng} J Med 1980; 302:91-92 10 Honey M, Cotter L, Davies N, Denison D. Clinical and hemodynamic effects of diazoxide in primary pulmonary hypertension. Thorax 1980; 35:269-76 11 Buch J, Wennevold A. Hazards cA diazoxide in pulmonary hypertension. Br Heart J 1981; 46:401-3 12 Cohen ML, KroDZOn I. Adverse hemodynamic efFects c1 phentolamine in primary pulmonary hypertension. Ann Intern Med 1981; 95:591-92 13 Parker M, Greenberg B, Massie B, Dash H. Deleterious effects ofhydralazine in patients with pulmonary hypertension. N Eng} J Med 1982; 306:1326-31 14 Naeije R, M6lot: C, Mols ~ Hallemans R. Reduction in pulmonary hypertension by prostaglandin E 1 in decompensated chronic obstructive pulmonary disease. Am Rev Respir Dis 1982;
.n:
125:1-5
15 Wagner PO, Nauman PF: Laravuso RB. Simultaneous measurement of eight foreign gases in blood by gas chromatography. J Appl Physioll974; 36:600-5. 16 Wagner PO, Saltzman HA, West JB. Measurement ofcontinuous distributions cAventilation-perfusion ratios:theory. J Appl Physioll974; 36:588-99 17 Evans ~ Wagner PD. Umits on VAlQ distributions from analysis mexperimental inert gas elimination. J Appl Physiol
1977; 42:889-98
18 West JB, Wagner PD. Pulmonary gas exchange. In: West JB, ed. Bioengineering aspects ~ the lung (vol 3). New York: Marcel Dekker, 1977:361-458 19 Gillard C, Gossart R, Neuforge A, Ostan B, Diercla J~ Mauroy M. Contribution to the study of chest and lung mechanics in artificially ventilated normal man during surgery. Acta Anesthesiol Belg 1975; 26(suppl):I9-42 20 Wagner PO, Laravuso RB, Uhl RR, West JB. Continuous distributions of ventilation-perfusion ratios in normal subjects breathing air and 1()()tf, 0 •. J Clin Invest 1974; 54:54-68 21 Askrog V. Changes in (a-A) COl difference and pulmonary artery Effecta d NItedIpIne on YentII8IionIPer (Mel« et eI)
pressure in anesthetized man. J Appl Physioll966; 2i: 1299-1305 22 Crevey BJ, Dantzker DR, Bower JS, Popat lCD, Walker SD. Hemodynamic and gaS exchange effects of intravenouS diltiazem 23
24 25
26 27
in patients with pulmonary hypertension. Am J Cardioll982; 49:572-83 Stone PH, Antmann EM, Muller JE, Braunwald E. Calcium channel blocking agents in the treatment of cardiovascular disorders. Part II: Hemodynamic effects and clinical applications. Ann Intern Med 1980; 93:886-904 Bohr DF. The pulmonary hypoxic response. Chest. 1977; 71(suppl):244-46 Simonneau G, EscoUJTOU ~ Duroux ~ Lockhart A. Inhibition of hypoxic pulmonary vasoconstriction by nifedipine. N Eng) J Med 1981; 304:1582-85 Camerini F, Alberti E, Klugmann S, Salvi A. Primary pulmonary hypertension: effects of nifedipine. Br Heart J 1980; 44:352-56 Landmark Ie, Refsum AM, Simonsen 5, 5torstein o. Verapamil
and pulmonary hypertension. Acta Med Scand 1978;
204:299-302 28 Kambara H, Fujimoto Ie, Wakabayashi A, Kawai C. Primary
pulmonary hypertension: beneficial therapy with diltiazem. Am Heart J 1981; 101:230-31 29 Watkins WD, Peterson MB, Crone RIC, Shannon DC, Levine L. Prostacyclin and prostaglandin E 1 for severe idiopathic pulmonary hypertension. Lancet 1980; 1:1083 30 Guz A, Noble MIM, Eisele JH, Trenchard D. Experimental results of vagal block in cardiopulmonary disease. In: Porter R, ed. Breathing: Hering-Breuer centenary symposium. London: J ~ A Churchill Ltd, 1970:315-29 31 Millard RW, Lathrop DA, Crupp G, Ashraf M, Crupp IL, Schwartz A. Differential cardiovascular effects of calcium channel blocking agents: potential mechanisms. Am J CardioI1982; 49:499-506
First World Congress on Cardiovascular Pharmacotherapy The First World Congress on Cardiovascular Pharmacotherapy will be held in Geneva, Switzerland, April 11-15. For information, contact Adam Schneeweiss, M.D., Scientific Secretary, c/o Interconference, 12 Ave des Amazones, 1224, Chene-Bourgeries, Geneva, Switzerland.
CHEST I 83 I 2 I February, 1883
207
'Ibe effects of nifedipine on hemodynamics and pulmonary gas exchange were investigated in two patients with primary pulmonary hypertension. After 10 mg of the drug taken sublinguaDy, pulmonary and systemic vascular resistances decreased, cardiac output increased, and blood oxygenation was improved. As assessed by the multiple inert gas elimination technique, oifedipine induced a deterioration in
increased perfusion of units with low WQ. In spite of this negative effect on gas exchange, arterial Po. increased as a consequence ofincreased mixed venous Po. in relation to an aagmented cardiac output, and in one patient there was a decrease in the secondary atrial shunt. Both patients were clinically improved by the nifedipine as a long-term treatment.
with primary pulmonary hypertension have widened alveolar-arterial POI gradients and may become hypoxemic in advanced stages of the disease, when cardiac output also falls. l Studies using the multiple inert gas elimination technique have provided a better understanding of the mechanisms of abnormal gas exchange in these patients, and show in particular that a pharmacologic reduction in pulmonary vascular tone deteriorates ventilation/perfusion (VAlQ) matching.1,3 This potentially deleterious effect of pulmonary vasodilation received little attention in most of the recent reports on vasodilator therapy in primary pulmonary hypertension. 4-13 On the other hand, vasodilators tested until now in primary pulmonary hypertension with variable success are not specific fur the pulmonary circulation and have also been occasionally associated with serious adverse effects. l().13 We observed favorable clinical results in two patients with primary pulmonary hypertension who were given nifedipine and have investigated the effects of this drug on hemodynamics as well as on pulmonary gas exchange.
admission, a right heart catheterization showed severe pulmonary hypertension, partially reversible after a prostaglandin E 1 (PGEJ infusion, 0.02 ....g/kg/min (1llble 1). Hydralazine, 50 mg given fOur times per day orally, did not affect the gradient between pulmonary artery pressures and wedge pressures, but induced a 45 percent reduction in pulmonary vascular resistances, and was therefOre attempted as a long-term treatment. The patient, howeveJ; soon discontinued use ofhydralazine because of side effects consisting c1 malaise, headache, nervousness, and frequent nausea. PhYSical examination on admission showed her to be healthy-looking, slightly cyanotic, with no distress at rest, 157 em tall and weighing 60 kg. Blood pressure was !WOO mm Hg, heart rate 68 beatslmin, rectal temperature 36.SO C, and respiratory rate 16 breaths/min. There was jugular distension with visible A waves. The
ventilation/perfusion (VAJQ) relationships consisting in an
~ents
CASE REPORTS CASE
I
A 61-yeaJ'oOld woman was adpUtted with a history of progressively severe exertional dyspnea and fatigue over the preceding ten years. She denied previous use of drugs and had never before had symptoms suggestive of cardiac or pulmonary disease. From three years befOre admission, exertional dyspnea had become invalidating (walking on level ground) and was accompanied by chest pain and palpitations and on four occasions by syncope. One year before *From the Medical Intensive Care Unit and the Department of Cardiology, Saint-Pierre University Hospital, BrusselS, Belgium ManUscript received May 10; revision accepted August 23. Reprint requests: Dr. Melot, St-Pierre Unicersity HoB'pital, Rue Haute 322, B-1000 Brussels, Belgium
lungs were clear. The heart had apalpable 5. and aparasternal heave.
A grade 2 pansystolic murmUJ; increased at inspiration, was heard along the left: stemal border. The second heart sound bad a loudly accentuated pulmonic component. There was no hepatomegaly, ascites, or peripheral edema. An ECG revealed a right axis deviation and a right ventricular hypertrophy. Chest roentgenogram showed enlarged pulmonary arteries, with attenuation of the peripheral vascular markings and an enlargement of the right ventricle. Results of plasma electrolyte and renal and liver function tests, complete blood count, and a coagulation profile were normal. There was no laboratory evidence of connective tissue disorder. A ventilation! perfusion lung scan showed no evidence of pulmonary thromboembolic disease. A pulmonary arteriogram disclosed DO 6lling defect in the pulmonary vasculature. Lung function tests were normal, except for a reduction in diffusion capacity for carbon monoxide at 12.9 mJI minlmm Hg. M mode and two-dimensional _ b y showed a normal-sized left ventricle, a dilated right ventricle with marked hypertrophy of ventricular walls, and a normal aortic and
mitral valves. Aprominent Bpoint was noted on the bicuspid valve,
the pulmonic valve E-F slope was reduced, and the A wave was absent; the pulmonic valve showed a midsystolic notch, forming a "we' pattem. Contrast echocardiography was performed using intravenous (IV) injection of 5 percent dextrose in water and demonstrated a right-to-Ieft atrial shunt. Right heart catheterization was perfOrmed according to a procedure reported elsewhere. " Hemodynamic and gasometric measurements were obtained in duplicate befOre and 60 minutes after nifedipine, 20 mg given sublingually. As shown in 18ble 1, the basal determinations were comparable to those one year befOre (except for an increase in right atrial pressures), indicating slow progression
m
CHEST I 83 I 2 I February, 1883
203
Table I-MetJft Valua ofDuplictJte HernotIr/ntJmk and Blood GGaa DetennintJdona in noo Patienta WIlla PritntJ'lI PulmontJrrI H~
can PeEn HydrtJlszine, and Nifediptne
Patient 1, 1st Catheterization
Patient 2,
2nd Catheterization
Patient 2
Baseline PGEI Hydralazine Baseline Nifedipine Baseline Nifedipine Normal Umits*
Variable Arterial pH Arterial Po., mm Hg Arterial Peo., mm Hg Mixed Venous Po., mm Hg O.lhmsport, mllminlml 0. Consumption mlIminlml P(A-a) 0" mm Hg· Venous admixture, (If,)t Cardiac index, Uminlm' Heart rate, beat/min Mean arterial pressure, mm Hg Systemic vascular resistance, dyne.s.em- 5 Mean right atrial pressure, mm Hg Mean pulmonary artery pressure, mm Hg Pulmonary artery wedge pressure, mm Hg Pulmonary vascular resistance, dyne.s.em- 5
7.46 46 27 27 292 125 70 34 1.9 75 76 1753 9 74 8 1756
7.45 56 29 35
7.46
63
25 37 568 136 56 22 3.3 92 75 1018 8 72
465 131 58 28 2.8 74 70 1140 7 53 8 787
9
963
7.48 42 26 25 320 133
77 34 2.0 75 78 1656 13 75
7
1733
7.48 49 27 30 470 147
69
29 2.8 95 58
SOl 14 62
8
1002
7.51 81 25 31 382 133 42 8 2.1 82 95 1828 7 53
5
992
7.55 85 22 37 615 130 41 10 3.4 116 82 1020 4 54
5 641
7.38 - 7.44 SO - 102 32 - 42 34 - 481 450 - 850 100 - 200 0-20 0.1 - 10 2.6 - 4.6 50 - 100 70 - 105 650 - 1350 1-9 8 - 20
5 -14
25 - 100
·Calculated using the ideal alveolar gas equation, assuming a respiratory ratio equal to 0.8. tCalculated as (capillary 0. content-arterial 0, content/capillary 0. content-mixed venous 0. content). *Ranges obtained from right heart catheterizations performed in 23 healthy volunteen.
eX the disease. Nifedipine induced pulmonary vasodilation, increases in cardiac index and 0. transport, and improvement in blood oxygenation. Between the two baseline and the two nifedipine measurements, arterial and mixed venous blood and mixed expired gas were sampled to determine VAlQ distributions by the multiple
•
1.0 LIMIN
~
'.02
c
0 0
~ 0
~: 12,.
N.R.9 .1 .FORE NIFIDlPI. .
0
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"predicted 141
mmHg
SHUNT
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was distributed to a mode around the units with a VAlQ ratio of 2.6.
VENTILATION ....
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i
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~: 11~
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predict ed I 48
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BLOOD FLOW"
The shape and position of this mode along the VAlQ axis were comparable to those eX normal subjects." There was an additional mode ofblood flow to units with low VAlQ ratios (11.9 percent of total blood flow to units with VAlQ<0.2). Dead space was normal (32 percent of tidal volume)... Shunt was 20 percent of total blood flow. It must be noted that the inert gas method does not allow differentiation between pulmonary and cardiac right-to-left shunt. After nifedipine, there was a deterioration in VAlQ relationships, with an increased perfusion to units with low VAlQ ratios (18.9 percent eX total blood flow to units with VAlQ<0.2). Shunt decreased to 10 percent. Dead space increased to 51 percent, probably in relation to the reduction in pulmonary pressure. II Before as well as after nifedipine, the absence of diffusion abnormality was conBrmed by the good agreement between measured and predicted arterial POI' After nine months eX treatment ~th nifedipine, 20 mg orally four times a day, the patient felt much better and enjoyed a nearly normal life. Her exertional dyspnea markedly decreased, and she had no chest pain and no syncope. She wu even able to dance again-her favorite pastime, which she had had to abandon eight yean previously. CASE 2
0 0
1.0 0.01 0.1 VENTILATION· PeRFUSION
10.0 RATIO
100.0
FIGURE 1. VAlQ distributions before and after nifedipine, 20 mg sublingually, in patient 1.
204
inert gas elimination technique as described by Wagner and coworken. J5.JI The least-squares analysis with enfOrced smoothing was used to minimize the effects of random experimental enor. 17 the VAlQ distributions were combined with the mixed venous blood gases, cardiac output, minute ventilation, and P50 in a lung model described by West and Wagner' to predict the arterial pressure eX oxygen assuming complete alveolar-end capillary equilibrium in each lung unit. Minute ventilation and respiratory rate were measured using a pneumotachograph eX the Fleisch type connected with an electronic integrator (AUPREM 91 A). ]I the VAlQ distributions before and after nifedipine are shown in Figure 1. Before nifedipine, the majority of pulmonary blood flow
This 38-YeaN»ld woman had been in good health until one year previously, when she had several syncopes at exertion. ThereafteJ; she stdJered from progressively severe exertional dyspnea, fatigue, - frequent palpitations, and an average eX one syncope at exertion EtrecII ~ NlfedlpIne on VentlI8IIonIPerfuIIo (Mel« et II)
every 15 days. Three months before admission, she bad an episode eX congestive heart failure and received treatment consisting mrest, diuretics, and digitalis. She denied previous use of drugs. Physical examination showed her to be healthy, eupneic, and noncyanotic, 168 em tall and weighing 71 kg. Blood pressure was 120180 DlDl Hg, heart rate 80 beatslmin, rectal temperature 36.SO C, and respiratory rate 16 breaths/min. Heart auscultation showed a markedly accentuated second heart sound and a grade 2 pansystolic murmur along the left sternal border. The remainder eX the examination was unremarbble. An ECG revealed a right axis deviation and a right venbicular hypertrophy. Chest roentgenogram showed enlarged pulmonary arteries, with attenuation of peripheral vascular markings and enlargement of the right venbicle. Results of plasma electrolyte and renal and liver function tests, complete blood count, and coagulation pro61e were normal. There was no laboratory evidence of connective
•o
increased, while mixed venous blood oxygenation returned to within
normal limits. The VAlQ distributions in patient 2 before and after nifedipine were determined according to the same study protocol as in patient 1 (Fig 2). Before nifedipine administration, the majority ofblood flow was disbibuted to a mode around the units with WQ ratio of I. 7, and there was an additional mode of blood flow to units with low WQ ratios (3.9 percel)t of total blood flow to units with WQ<0.2). Dead space was normal, at 37 percent of tidal volume. The shunt was negligible (0.7 percent of total blood flow). After nifedipine administration, the perfusion of units with low VAlQ ratios was increased (to 9.4 percent of total blood flow to units with VAlQ
Dantzker and Bower have recently shown by the multiple inert gas elimination technique that VAl¢. relationships in patients with chronic obliterative pulmonary vascular disease (idiopathic or secondary to recUJTent pulmonary emboli) are only minimally abnormal, with a mean of 10 percent of cardiac output perfusing units with low VAI¢.. The same authors demonstrated that in such patients reduction of pulmonary vascular tone by an infusion of nitroprusside or
LIIiIN
"me.lured ••1 '.02 'predicted. mmHI 11
~
o
o II ;
~: 37,.
e.G. 9 31 .'OM NI'EDIPI. .
Q
0.5 VENTILATION .-.
Z
o
t=
c
~
t=
SHUNT
z
~
o
1
,
.0.7~ ~R58I""~",MIf1"
0.~1
o
ci.1 1:0 V!NTllATION • PERFUSION
10.0 RATIO
1.0 LIIiIN
tissue disorder. Ventilation/perfusion lung scan and pulmonary
arteriogram showed no evidence of pulmonary thromboembolic disease. Lung function tests were normal, excepted fOr a reduction in the diffusion capacity fOr carbon monoxide at 17.8 mlImin1mm Hg. M-mode and two-dimensional echocardiography showed a normalsized left ventricle, normal aortic and mitral valves, and a markedly dilated right venbicle. The pulmonic valve E-F slope was reduced, and the A wave was almost absent; a midsystolic notch was apparent. Contrast echocardiography disclosed no atrial or ventricular rightto-Ieft shunt. Right heart catheterization (18ble 1) showed marked pulmonary hypertension, normal 6lling pressures of the heart, and a 10\;Vered cardiac output. Arterial Po. was normal in the presence of marked alveolar hyperventilation and respiratory alkalosis. The 0. transport and mixed venous Po. were lmv. Administration of nifedipine, 20 mg sublingually, did not change pulmonary artery pressures, but increased cardiac output and 0. transport, while pulmonary vascular resistances were reduced by 33 percent. Arterial oxygenation
\0
C.G. 9 38 unR NIF!D. . . .
"" me.lured • IS '.02....... mmHg predicted. 14
Q
o
o
iii
.. o.s
o
~
t=
c~
BLOOD FLOW'-'
t=z
SHUNT
1&1
>
o
1
.0
o
FIGURE
0.01 0.1 1.0 VENTilATION· PERFUSION
10.0 RA'TIO
100.0
2. VAlQ distributions befOre and after nifedipine, 20
mg sublinguaUy, in patient 2.
isoproterenol deteriorates gas exchange without nega-
tive effect on arterial oxygenation, because mixed
venous POI is increased as a consequence of increased cardiac output. 3 Our observations are in agreement with these studies. We manipulated the lung model used to predict arterial PoI J8 and quantified the nifedipine-induced changes (Uble 2). It is apparent that negative effects on gas exchange by pulmonary vasodilation were slightly overcompensated by positive effects of increased cardiac output (and reduction of atrial right-to-Ieft shunt in patient 1). Crevey et alII observed no modiJication in VAl¢. relationships in 6ve patients with pulmonary hypertension (which was primary in four of them) after diltiazem administration, but this was probably due to the absence of physiologi-
cally relevant hemodynamic changes. Table !-TIaeoreticGl EJfecta rfN~-inducetl
eMng. on A.rwritJl Po. in &0 PadenII Wtda PritntJ,." PulrnontJ'lI H"".,.,..,.
\Baseline Arterial PO.
Patient 1
Patient 2 41 mm Hg 81 mm Hg
Nifedipine-induced changes -3 mm Hg-13 mm Hg VAlQ deterioration Shunt decrease +4mmHg 0 Mixed venous Po. increase due to cardiac output increase +6 mm Hg+ 18 mm Hg 48 mm Hg 84 mm Hg Resulting arterial Po. CHEST I 83 121 February, 1183
201
Calcium channel-blocking agents can influence cardiovascular hemodynamics by a complex interplay of systemic arterial vasodilation, a negative inotropic effect, and reflex phenomena. Among these drugs available for clinical use, nifedipine has been shown to be the most potent when administered in equal doses by weight to isolated tissue preparations. 13 In vivo, marked systemic vasodilation by nifedipine elicits a padrenergic response that accounts for an increase in cardiac output and an acceleration in heart rate, as observed in our patients. Pulmonary vasoconstriction is dependent on the availability of calcium to the effector cells, i4 and calcium channel-blockers have thus also been tried to induce pulmonary vasodilation in patients with primary or secondary pulmonary hypertension. A well-tolerated reduction in pulmonary vascular tone by nifedipine has been reported by Simonneau et allll in patients with decompensated chronic obstructive pulmonary disease, and by Camerini et aI18 in one patient with primary pulmonary hypertension. Verapamil was less effective in the study by Landmark et alIT in 12 patients with pulmonary hypertension (which was primary in nine of them). Pulmonary artery pressures decreased as a consequence of decreased cardiac output, and pulmonary vascular resistances remained unchanged. In the patients ofCrevey et al,2I diltiazem induced at rest only a slight decrease in pulmonary artery pressures, without change in cardiac output or in pulmonary vascular resistances. Kambara et alJ8 reported a marked pulmonary vasodilation by diltiazem in a younger patient. Thus, the available data on a limited number of patients suggest that nifedipine, and diltiazem to a lesser degree, may present an interesting effectiveness/toxicity ratio in the treatment of primary pulmonary hypertension. PGE. has been effective in reducing pulmonary hypertension, without side effects or excessive systemic vasodilation, in patients with decompensated chronic obstructive pulmonary disease·" and in one patient with primary pulmonary hypertension. J9 In our patient 1, PGE. appeared to be a more active pulmonary vasodilator than hydralazine. PGE. is regrettably not available for oral use, but may be helpful at right heart catheterization to determine the functional part of pulmonary hypertension. How did nifedipine treatment improve the clinical state in our patients? Their absolute level ofpulmonary artery pressures decreased moderately (17 percent in patient 1) or did not change at all (patient 2), but cardiac output increased in both. Limitation of cardiac output because of obstruction to flow through the lungs is likely to account at least in part for exertional dyspnea, syncope, and sudden death in advanced primary pulmonary hypertension.· In this respect, a pharmacologic increase in cardiac output, even without fall 208
in pulmonary artery pressures, may be the main
hemodynamic event leading to symptomatic improvement. 1 Another tentative explanation for the reduction in dyspnea in our patients might be a vagolytic effect of nifedipine that would reduce the afferent discharges from intrapulmonary mechanoreceptors. 3O•31 REFERENCES
n:
1 Voelkel N, Reeves Primary pulmonary hypertension. In: Moser ~M, edt Pulmonary vascular disease. New York: Marcel Dekker, 1979; 573-628 2 DantzkerDR, BowerJS. Mechanisms of gas exchangeabnonnality in patients with chronic obliterative pulmonary vascular disease. J Clin Invest 1979; 64:1050-55 3 Dantzker DR, Bower JS. Pulmonary vascular tone improves VAl Q matching in obliterative pulmonary hypertension. J Appl Physioll981; 51:607-13 4 Reeves fI: Hope in primary pulmonary hypertension. N Eng! J Med 1980; 302:112-13 5 Ellcayam U. Vasodilator therapy in primary pulmonary hypertension. Chest 1981; 79:253-54 6 Rubin LJ, Peter RH. Oral hydralazine therapy for primary pulmonary hypertension. N Eng} J Med 1980; 302:69-73 7 Ruskin IN, Hutter AM. Primary pulmonary hypertension treated with oral phentolamine. Ann Intern Med 1979; 90:772-74 Kelly DB. Isoproterenol as a potential 8 Daoud FS, Reeves pulmonary vasodilator in primary pulmonary hypertension. Am J Cardioll978; 42:817-22 9 Klinke W~ Gilbert JAL. Diazoxide in primary pulmonary hypertension. N Eng} J Med 1980; 302:91-92 10 Honey M, Cotter L, Davies N, Denison D. Clinical and hemodynamic effects of diazoxide in primary pulmonary hypertension. Thorax 1980; 35:269-76 11 Buch J, Wennevold A. Hazards cA diazoxide in pulmonary hypertension. Br Heart J 1981; 46:401-3 12 Cohen ML, KroDZOn I. Adverse hemodynamic efFects c1 phentolamine in primary pulmonary hypertension. Ann Intern Med 1981; 95:591-92 13 Parker M, Greenberg B, Massie B, Dash H. Deleterious effects ofhydralazine in patients with pulmonary hypertension. N Eng} J Med 1982; 306:1326-31 14 Naeije R, M6lot: C, Mols ~ Hallemans R. Reduction in pulmonary hypertension by prostaglandin E 1 in decompensated chronic obstructive pulmonary disease. Am Rev Respir Dis 1982;
.n:
125:1-5
15 Wagner PO, Nauman PF: Laravuso RB. Simultaneous measurement of eight foreign gases in blood by gas chromatography. J Appl Physioll974; 36:600-5. 16 Wagner PO, Saltzman HA, West JB. Measurement ofcontinuous distributions cAventilation-perfusion ratios:theory. J Appl Physioll974; 36:588-99 17 Evans ~ Wagner PD. Umits on VAlQ distributions from analysis mexperimental inert gas elimination. J Appl Physiol
1977; 42:889-98
18 West JB, Wagner PD. Pulmonary gas exchange. In: West JB, ed. Bioengineering aspects ~ the lung (vol 3). New York: Marcel Dekker, 1977:361-458 19 Gillard C, Gossart R, Neuforge A, Ostan B, Diercla J~ Mauroy M. Contribution to the study of chest and lung mechanics in artificially ventilated normal man during surgery. Acta Anesthesiol Belg 1975; 26(suppl):I9-42 20 Wagner PO, Laravuso RB, Uhl RR, West JB. Continuous distributions of ventilation-perfusion ratios in normal subjects breathing air and 1()()tf, 0 •. J Clin Invest 1974; 54:54-68 21 Askrog V. Changes in (a-A) COl difference and pulmonary artery Effecta d NItedIpIne on YentII8IionIPer (Mel« et eI)
pressure in anesthetized man. J Appl Physioll966; 2i: 1299-1305 22 Crevey BJ, Dantzker DR, Bower JS, Popat lCD, Walker SD. Hemodynamic and gaS exchange effects of intravenouS diltiazem 23
24 25
26 27
in patients with pulmonary hypertension. Am J Cardioll982; 49:572-83 Stone PH, Antmann EM, Muller JE, Braunwald E. Calcium channel blocking agents in the treatment of cardiovascular disorders. Part II: Hemodynamic effects and clinical applications. Ann Intern Med 1980; 93:886-904 Bohr DF. The pulmonary hypoxic response. Chest. 1977; 71(suppl):244-46 Simonneau G, EscoUJTOU ~ Duroux ~ Lockhart A. Inhibition of hypoxic pulmonary vasoconstriction by nifedipine. N Eng) J Med 1981; 304:1582-85 Camerini F, Alberti E, Klugmann S, Salvi A. Primary pulmonary hypertension: effects of nifedipine. Br Heart J 1980; 44:352-56 Landmark Ie, Refsum AM, Simonsen 5, 5torstein o. Verapamil
and pulmonary hypertension. Acta Med Scand 1978;
204:299-302 28 Kambara H, Fujimoto Ie, Wakabayashi A, Kawai C. Primary
pulmonary hypertension: beneficial therapy with diltiazem. Am Heart J 1981; 101:230-31 29 Watkins WD, Peterson MB, Crone RIC, Shannon DC, Levine L. Prostacyclin and prostaglandin E 1 for severe idiopathic pulmonary hypertension. Lancet 1980; 1:1083 30 Guz A, Noble MIM, Eisele JH, Trenchard D. Experimental results of vagal block in cardiopulmonary disease. In: Porter R, ed. Breathing: Hering-Breuer centenary symposium. London: J ~ A Churchill Ltd, 1970:315-29 31 Millard RW, Lathrop DA, Crupp G, Ashraf M, Crupp IL, Schwartz A. Differential cardiovascular effects of calcium channel blocking agents: potential mechanisms. Am J CardioI1982; 49:499-506
First World Congress on Cardiovascular Pharmacotherapy The First World Congress on Cardiovascular Pharmacotherapy will be held in Geneva, Switzerland, April 11-15. For information, contact Adam Schneeweiss, M.D., Scientific Secretary, c/o Interconference, 12 Ave des Amazones, 1224, Chene-Bourgeries, Geneva, Switzerland.
CHEST I 83 I 2 I February, 1883
207