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DOI 10.1378/chest.83.2.203 1983;83;203-207Chest
C Mélot, R Naeije, P Mols, J L Vandenbossche and H Denolin matching in primary pulmonary hypertension.Effects of nifedipine on ventilation/perfusion
http://chestjournal.chestpubs.org/content/83/2/203
can be found online on the World Wide Web at: The online version of this article, along with updated information and services
) ISSN:0012-3692http://chestjournal.chestpubs.org/site/misc/reprints.xhtml(without the prior written permission of the copyright holder.reserved. No part of this article or PDF may be reproduced or distributedChest Physicians, 3300 Dundee Road, Northbrook, IL 60062. All rights
ofbeen published monthly since 1935. Copyright1983by the American College is the official journal of the American College of Chest Physicians. It hasChest
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5From the Medical Intensive Care Unit and the Department of
Cardiology Saint-Pierre University Hospital, Brussels, BelgiumManuscript received May 10; revision accepted August 23.Reprint requests: Dr Melot, St-Pierre University Hospital, RueHaute 322, B-1000 Brussels, Belgium
CHEST / 83 / 2 / Fetruar� 1983 203
Effects of Nifedipine on Ventilation!Perfusion Matching in Primary PulmonaryHypertension*Christian Melot, M.D.; Robert Nae�je, M.D.; Pierre Mols, M.D.;
Jean-Luc Vandenbossche, M.D.; and Henri Denolin, M.D., Ph.D.
The effects of nifedipine on hemodynamics and pulmonarygas exchange were investigated in two patients with primary
pulmonary hypertension. After 20 mg of the drug takensublingually, pulmonary and systemic vascular resistances
decreased, cardiac output increased, and blood oxygenation
was improved. As assessed by the multiple inert gaselimination technique, nifedipine induced a deterioration in
ventilation/perfusion (WQ) relationships consisting in an
patients with primary pulmonary hypertension have
widened alveolar-arterial Po, gradients and may
become hypoxemic in advanced stages of the disease,
when cardiac output also falls.’ Studies using the
multiple inert gas elimination technique have pro-
vided a better understanding of the mechanisms of
abnormal gas exchange in these patients, and show in
particular that a pharmacologic reduction in pulmo-
nary vascular tone deteriorates ventilation/perfusion
(V�JQ) matching.”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’�
On the other hand, vasodilators tested until now in
primary pulmonary hypertension with variable suc-
cess are not specific for the pulmonary circulation and
have also been occasionally associated with serious
adverse effects.10u
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 ex-
change.
CAsE 1
CASE REPORTS
A 61-year-old woman was admitted with a history of progressively
severe exortional 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 andpalpitations and on four occasions by syncope. One year before
increased perfusion of units with low VAJQ. In spite of thisnegative effect on gas exchange, arterial Po, increased as a
consequence of increased mixed venous Po5 in relation to an
augmented cardiac output, and in one patient there was a
decrease in the secondary atrial shunt. Both patients wereclinically improved by the nifedipine as a long-term treat-
ment,
admission, a right heart catheterization showed severe pulmonary
hypertension, partially reversible after a prostaglandin E, (PGE,)
infusion, 0.02 p.glkg/min (Table 1).
Hydralazine, 50 mg given four times per day orally, did not affect
the gradient between pulmonary artery pressures and wedge
pressures, but induced a45 percent reduction in pulmonary vascular
resistances, and was therefore attempted as a long-term treatment.
The patient, however, soon discontinued use of hydralazine because
of side effects consisting of malaise, headache, nervousness, and
frequent nausea. Physical examination on admission showed her to
be healthy-looking, slightly cyanotic, with no distress at rest, 157cm
tall and weighing 60kg. Blood pressure was 111160mm Hg, heart rate
68 beats/mm, rectal temperature 36.8#{176}C, and respiratory rate 16
breaths/mm. There was jugular distension with visible A waves. The
lungs were clear. The heart had a palpable S2 and a parasternal heave.A grade 2 pansystolic murmur, increased at inspiration, was heard
along the left sternal border. The second heart sound had a loudly
accentuated pulmonic component. There was no hepatomegaly,ascites, or peripheral edema. An ECG revealed a right axis deviation
and a right ventricular hypertmphy. Chest mentgenograin showed
enlarged pulmonary arteries, with attenuation of the peripheralvascular markings and an enlargement of the right ventricle. Resultsof 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 thmmboem-
bolic disease. A pulmonary arteriogram disclosed no filling defect in
the pulmonary vasculature. Lung function tests were normal, except
fur a reduction in diffusion capacity for carbon monoxide at 12.9 ml/
mm/mm Hg. M mode and two-dimensional echocardiography
showed a normal-sized left ventricle, a dilated right ventricle withmarked hypertrophy of ventricular walls, and a normal aortic and
mitral valves. A prominent B point was noted on the tricuspid valve,
the pulmonic valve E-F slope was reduced, and the A wave was
absent; the pulmonic valve showed a midsystolic notch, funning a
..W” pattern. Contrast echocardiography was performed using
intravenous (IV) injection of 5 percent dextrose in water and
demonstrated a right-to-left atrial shunt.
Right heart catheterization was performed according to a proce..
dure reported elsewhere.’4 Hemodynamic and gasometric measure-
ments were obtained in duplicate before and 60 minutes after
nifedipine, 20mg given sublingually. As shown in lIble 1, the basal
determinations were comparable to those of one year before (exceptfur an increase in right atrial pressures), indicating slow progression
© 1983 American College of Chest Physicians by guest on July 14, 2011chestjournal.chestpubs.orgDownloaded from
of the disease. Nifedipine induced pulmonary vasodilation, in-
creases 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 VA/C) distributions by the multiple
1.0 L/MIN
N. R. 9 61 BEFORE NIFEDIPINE .-�: 32%VT
..measursd 42�02 mmHg
pr.dlct.d 41
0.5 SHUNT
20%
VENTILATION -
BLOOD FLOWN
0
0
0-I
a00
0
z0I-
-J
I-zUa.
1.0 L/MIN
0-IU.
000�2m- 0.60
z0I#{149}#{149}
�1I-z
0
-- III SSS#{149}#{149}
icioRATIO
l0&o
-: 51%V.,.
0.1 1.0
VENTILATION - PERFUSION
N. R. 9 61 AFTER NIFEDIPINE
measured 49Pi02 mmHg
�- pr.dlctsd 48
SHUNT
S 10%
VENTILATION
“ 0�1
VENTILATION . PERFUSION
11.0 io6.o
RATIO
Ficuas 1. VAJQ distributions before and after nifedipine, 20mg sublingually, in patient 1.
204 Effects ot Nifedipine on Venthatton/Perfuslon (Me!ot eta!)
Table 1-Mean Values of Duplicate Hemodynamic and Blood Gases Determinations in Two Patients With Primary Pulmonary
Hypertension Given PGEI, Hydralazine, and N�fedipine
Variable
1stPatient 1,
CatheterizationPatient 2,
2nd Catheterization
Baseline
Patient 2
Nifodipine Normal UmitslBaseline PCE, Hydralazine Baseline Nifedipine
Arterial pH 7.46 7.45 7.46 7.48 7.48 7.51 7.55 7.38 - 7.44
Arterial Po,, mm Hg 46 56 63 42 49 81 85 80-102
Arterial Pco,, mm Hg 27 29 25 26 27 25 22 32 -42
Mixed Venous P0,, mm Hg 27 35 37 25 30 31 37 34 - 4810, 1l�ansport, mI/minim’ 292 465 568 320 470 382 615 450 - 850
0, Consumption mI/min/m’ 125 131 136 133 147 133 130 100 - 200
P(A-a) 02, mm Hg* 70 58 56 77 69 42 41 0 - 20
Venous admixture, (%)t 34 28 22 34 29 8 10 0.1 - 10
Cardiac index, IJmin/m’ 1.9 2.8 3.3 2.0 2.8 2.1 3.4 2.6 - 4.6
Heart rate, beatimmn 75 74 92 75 95 82 116 50 - 100
Mean arterial pressure, mm Hg 76 70 75 78 58 95 82 70 - 105
Systemic vascular resistance, dyne.s.cm’ 1753 1140 1018 1656 801 1828 1020 650 - 1350
Mean right atrial pressure, mm Hg 9 7 8 13 14 7 4 1 - 9
Mean pulmonary artery pressure, mm Hg 74 53 72 75 62 53 54 8 - 20
Pulmonary artery wedge pressure, mm Hg 8 8 9 7 8 5 5 5 - 14
Pulmonary vascular resistance, dyne.s.cm’ 1756 787 963 1733 1002 992 641 25 - 100
5Calculated 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).
lRanges obtained from right heart catheterizations performed in 23 healthy volunteers.
inert gas elimination technique as described by Wagner and cowork-
ers.”” The least-squares analysis with enforced smoothing was used
to minimize the effects of random experimental error.’7 The VA/C)
distributions were combined with the mixed venous blood gases,
cardiac output, minute ventilation, and P,� in a lung model described
by West and Wagner” to predict the arterial pressure of oxygen
assuming complete alveolar-end capillary equilibrium in each lung
unit. Minute ventilation and respiratory rate were measured using a
pneumotachograph of the Fleisch type connected with an electronic
integrator (AUPREM 91 A).”
The ‘/A/C) distributions before and after nifedipine are shown in
Figure 1. Before nifedipine, the majority of pulmonary blood flow
was distributed to a mode around the units with a ‘/A/C) ratio of 2.6.The shape and position of this mode along the VA/C) axis were
comparable to those of normal subjects.� There was an additionalmode of blood flow to units with low VA/C) ratios (11.9 percent of total
blood flow to units with VA/Q<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 differentia-
tion between pulmonary and cardiac right-to-left shunt. After
nifedipine, there was a deterioration in VA/C) relationships, with an
increased perfusion to units with low Vi,./Q ratios (18.9 percent of
total blood flow to units with VA/Q<0.2). Shunt decreased to 10
percent. Dead space increased to 51 percent, probably in relation to
the reduction in pulmonary pressure.” Before as well as after
nifedipine, the absence of diffusion abnormality was confirmed by
the good agreement between measured and predicted arterial Po,.After nine months of treatment with nifedipine, 20mg 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 was even able to dance again-her
favorite pastime, which she had had to abandon eight years previ-
ously.
CASE 2
This 38-year-old woman had been in good health until one year
previously, when she had several syncopes at exertion. Thereafter,
she suffered from pmgressively severe exertional dyspnea, fatigue,
frequent palpitations, and an average of one syncope at exertion
© 1983 American College of Chest Physicians by guest on July 14, 2011chestjournal.chestpubs.orgDownloaded from
CO. 9 38 BEFORE NIFEDIPINEV
37%
81P.O2 mmHg
‘�-pr.dIct.d 81
VENTILATION -
SHUNT
#{149}O.7%
0
0-JU.
a00
0.5
0U.
a00-J
0
z0I-
I-zUa.
0.01 0.1 1.0
VENTILATION - PERFUSION RATIO
1.0 L/MIN
CO. 938 AFTER NIFEDIPINE
m.a.ur.d 85P.O2 mmHg
“‘predIcted 84
V0
32%
VENTILATION -
BLOOD FLOW
10.0 100.0
RATIO
1.0 L/MIN
CHEST / 83 / 2 / February, 1983 205
every 15 days. Three months before admission, she had an episode ofcongestive heart failure and received treatment consisting of rest,
diuretics, and digitalis. She denied previous use of drugs. Physicalexamination showed her to be healthy, eupneic, and noncyanotic,168 cm tall and weighing 71kg. Blood pressure was 120/80mm Hg,
heart rate 80 beats/mm, rectal temperature 36.8#{176}C, and respiratory
rate 16 breaths/min. Heart auscultation showed a markedly accentu-
ated second heart sound and a grade 2 pansystolic murmur along theleft sternal border. The remainder of the examination was unre-
markable.
An ECG revealed a right axis deviation and a right ventricular
hypertrophy. Chest roentgenogram showed enlarged pulmonaryarteries, with attenuation of peripheral vascular markings and
enlargement of the right ventricle. Results of plasma electrolyte andrenal and liver function tests, complete blood count, and coagulationprofile were normal. There was no laboratory evidence of connective
tissue disorder. Ventilation/perfusion lung scan and pulmonaryarteriogram 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 ml/min/mm Hg.
M-mode and two-dimensional echocardiography showed a normal-sized left ventricle, normal aortic and mitral valves, and a markedly
dilated right ventricle. 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 right-
to-left shunt.
Right heart catheterization (ilible 1) showed marked pulmonaryhypertension, normal filling pressures of the heart, and a lowered
cardiac output. Arterial Po, was normal in the presence of markedalveolar hyperventilation and respiratory alkalosis. The 0, transport
and mixed venous Po, were low. Administration of nifedipine, 20 mg
sublingually, did not change pulmonary artery pressures, but in-
creased cardiac output and 0, transport, while pulmonary vascularresistances were reduced by 33 percent. Arterial oxygenation
increased, while mixed venous blood oxygenation returned to within
normal limits.
The VA/C) distributions in patient 2 before and after nifedipmnewere determined according to the same study protocol as in patient 1
(Fig 2). Before nifedipine administration, the majority of blood flowwas distributed to a mode around the units with VA/C) ratio of 1.7, and
there was an additional mode of blood flow to units with lowVA/C) ratios (3.9 percent of total blood flow to units with \ftiC)<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 adminis-tration, the perfusion of units with low VA/C) ratios was increased (to
9.4 percent of total blood flow to units with VA/C)<0.2). Dead spaceslightly decreased to 32 percent of tidal volume, a probably insignifi-
cant change, in relation to the absence of modification in pulmonary
artery pressures. There was no shunt. A good agreement was found
between measured and predicted arterial Po,, before as well as afternifedipine, indicating the absence of impaired diffusion.
After seven months of treatment with nifedipine, 20mg orally fourtimes per day the patient had no syncope, and exertional dyspneadecreased to the point that she was able to enjoy swimming again.
DISCUSSION
Dantzker and Bower’ have recently shown by the
multiple inert gas elimination technique that VA1()
relationships in patients with chronic obliterative pul-monary vascular disease (idiopathic or secondary to
recurrent pulmonary emboli) are only minimally ab-
normal, with a mean of 10 percent of cardiac output
perfusing units with low VA/Q. The same authors
demonstrated that in such patients reduction ofpulmo-
nary vascular tone by an infusion of nitroprusside or
0.1 1.0VENTILATION - PERFUSION
FIGURE 2. VA/Q distributions before and after nifedipine, 20
mg sublingually, in patient 2.
isoproterenol deteriorates gas exchange without nega-tive effect on arterial oxygenation, because mixed
venous Po, 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 Po,’8 and quantified the
nifedipine-induced changes (‘I#{224}ble2). It is apparent
that negative effects on gas exchange by pulmonary
vasodilation were slightly overcompensated by posi-
tive effects of increased cardiac output (and reduction
of atrial right-to-left shunt in patient 1). Crevey et a!”
observed no modification in VAR) relationships in five
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 2-Theoretical Effects of Nifedi pine-induced
Changes on Arterial P0, in Two Patients With Primary
Pulmonary Hypertension
�Basehne Arterial Po,Patient 1 Patient 241 mm Hg 81 mm Hg
Nifedipine-induced changes
VA/Q deterioration -3 mm Hg -15 mm HgShuntdecrease +4mm Hg 0Mixed venous Po, increasedue to cardiac output increase + 6 mm Hg + 18 mm Hg
Resulting arterial Po, 48 mm Hg 84 mm Hg
© 1983 American College of Chest Physicians by guest on July 14, 2011chestjournal.chestpubs.orgDownloaded from
206 Effects of Nifedipine on Venthatfon/Perfusion (M&ot et at)
Calcium channel-blocking agents can influence car-
diovascular 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.n In vivo,
marked systemic vasodilation by nifedipine elicits a f3-
adrenergic 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,’4 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 pulmo-
nary vascular tone by nifedipine has been reported by
Simonneau et a!” in patients with decompensated
chronic obstructive pulmonary disease, and by Cam-
erini et al” in one patient with primary pulmonary
hypertension. Verapamil was less effective in the study
by Landmark et al’7 in 12 patients with pulmonary
hypertension (which was primary in nine of them).
Pulmonary artery pressures decreased as a conse-
quence of decreased cardiac output, and pulmonary
vascular resistances remained unchanged. In the pa-
tients of Crevey et a!,” diltiazem induced at rest only a
slight decrease in pulmonary artery pressures, without
change in cardiac output or in pulmonary vascular
resistances. Kambara et al” reported a marked pulmo-
nary 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 effective-
ness/toxicity ratio in the treatment of primary pulmo-
nary hypertension.
PGE, has been effective in reducing pulmonary
hypertension, without side effects or excessive sys-
temic vasodilation, in patients with decompensated
chronic obstructive pulmonary disease’4 and in one
patient with primary pulmonary hypertension.”In our
patient 1, PGE, appeared to be a more active pulmo-
nary vasodilator than hydralazine. PGE, is regrettably
not available for oral use, but may be helpful at right
heart catheterization to determine the functional partof pulmonary hypertension.
How did nifedipine treatment improve the clinical
state in our patients? Their absolute level of pulmonary
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 primarypulmonary hypertension.’ In this respect, a phar-
macologic increase in cardiac output, even without fall
in pulmonary artery pressures, may be the main
hemodynamic event leading to symptomatic improve-
ment.’ 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 .
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CHESTI83/2/February,1983 207
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DOI 10.1378/chest.83.2.203 1983;83; 203-207Chest
C Mélot, R Naeije, P Mols, J L Vandenbossche and H Denolinhypertension.
Effects of nifedipine on ventilation/perfusion matching in primary pulmonary
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