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

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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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Switzerland.

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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