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Diffusing capacity of the lung and nifedipine in systemic sclerosis.

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1634
DIFFUSING CAPACITY OF THE LUNG AND
NIFEDIPINE IN SYSTEMIC SCLEROSIS
PETROS P. SFIKAKIS, MICHAEL KYRIAKIDIS, CONSTANTINE VERGOS, SOTIRIOS PAPAZOGLOU,
FOTIS GEORGIAKODIS. PAVLOS TOUTOUZAS, and PAUL SFIKAKIS
Lung involvement in systemic sclerosis may be
due in part to a functional abnormality of the pulmonary vasculature. To investigate the possible role of a
pulmonary vasospastic process in this disorder, 21 nonsmoking patients who had no evidence of cardiac disease
or pulmonary hypertension were evaluated with pulmonary function tests prior to administration of nifedipine,
30 minutes after a single oral dose of nifedipine (20 mg),
and after 4 weeks of treatment with nifedipine (10 mg 3
times daily). Treatment with nifedipine did not significantly change any of the pulmonary function values,
except for the carbon monoxide diffusing capacity
(DLco). The linear trend between the individual DLCO
values at baseline and their changes immediately following the initial 20-mg dose of nifediphe (r = -0.603, P =
0.02) and after 4 weeks of treatment (r = -0.636, P =
0.01) showed that the lower the DLco value at baseline,
the greater the improvement caused by nifedipine.
These findings support the hypothesis of a potentially
From the First Department of Propedeutic Medicine (Laiko
General Hospital) and the Cardiac Department (Hippokration Hospital), Athens University School of Medicine, and the Chest Unit,
Naval Hospital of Athens, Athens, Greece.
Petros P. Sfikakis, MD: Predoctoral Candidate, Chest Unit,
Naval Hospital of Athens, and Cardiac Department, Hippokration
Hospital; Michael Kyriakidis, MD: Assistant Professor of Cardiology, Cardiac Department, Hippokration Hospital; Constantine Vergos, MD: Head, Chest Unit, Naval Hospital of Athens; Sotirios
Papazoglou, MD: Senior Registrar, Cardiac Department, Hippokration Hospital; Fotis Georgiakodis, PhD: Biostatistics, First Department of Propedeutic Medicine, Laiko General Hospital; Pavlos
Toutouzas, MD: Professor of Cardiology, Cardiac Department,
Hippokration Hospital; Paul Sfikakis, MD: Professor of Medicine,
First Department of Propedeutic Medicine, Laiko General Hospital.
Address reprint requests to Petros P. Sfikakis, MD, Laiko
General Hospital, First Department of Propedeutic Medicine, 17,
Ag. Thoma str., Goudi 11527, Athens, Greece.
Submitted for publication January 5 , 1990; accepted in
revised form May 15, 1990.
Arthritis and Rheumatism, Vol. 33, No. 11 (November 1990)
reversible pulmonary vasospasm in systemic sclerosis
and suggest that nifedipine may be useful in the treatment of lung disease in these patients; however, further
studies are needed.
When pulmonary function is tested in patients
with systemic sclerosis, the carbon monoxide diffusing
capacity (DLco) is found to be reduced in most of
them (1,2). This reduction may represent either reduced alveolar capillary surface area available for gas
transfer because of interstitial fibrosis or the presence
of a primary vascular lesion, unrelated to fibrosis,
obliterating many of the small pulmonary vessels and
capillaries (3). Emmanuel et al noted lower DLco
values in patients with systemic sclerosis during the
cold winter months than during the warm summer
months; they speculated that cold-induced vasospasm
of the pulmonary vasculature might account for these
changes (4). Rodnan et a1 reported that similar histologic changes develop in the digital and pulmonary
arteries of patients with systemic sclerosis and longstanding Raynaud’s phenomenon, suggesting that
repetitive episodic spasm occurs in both vascular
beds (5).
Since a functional abnormality of the pulmonary vasculature may contribute to the pulmonary
vascular disease in systemic sclerosis, treatment with
vasodilating drugs might be beneficial in patients with
lung involvement and impaired diffusing capacity.
Recently, we found that administration of the calciumchannel blocking agent nifedipine immediately decreased pulmonary vascular resistance in all our patients with systemic sclerosis and normal cardiac
function (unpublished observations). Moreover, the
efficacy of nifedipine in the treatment of vasospastic
conditions, such as vasospastic angina (6,7), as well as
NIFEDIPINE IN SYSTEMIC SCLEROSIS
in the treatment of digital vasospasm in Raynaud’s
phenomenon (8,9), is well documented.
The present study was conducted to assess the
short-term, as well as the long-term, effects of nifedipine on the diffusion properties of the lung in patients with systemic sclerosis and to evaluate, if possible, the relative importance of pulmonary vasospasm
in this disorder.
PATIENTS AND METHODS
Patients. Twenty-one patients with definite progressive systemic sclerosis according to the American Rheumatism Association criteria (10) were studied. All patients met
the single major criterion for classification as having definite
progressive systemic sclerosis (proximal scleroderma) (10).
Ten patients were classified as having diffuse cutaneous
systemic sclerosis and the remaining 11 patients had the
limited cutaneous form, according to the classification by
LeRoy et a1 (1 1).
Selection of patients was based on their willingness
to participate in the study and their ability to undergo
pulmonary function testing. Patients were excluded if they
had a history of smoking or a history of symptoms attributable to chronic obstructive pulmonary disease. In addition,
patients were excluded if they had important renal involvement (serum creatinine concentration > 110 mmolesAiter) or
if they had systemic hypertension, ischemic heart disease,
valvular heart disease, or heart failure. None of the 21
patients had ever taken medication for pulmonary or cardiac
disease, including nifedipine. Four patients had been taking
low-dose steroids for 6-12 months. Dosages of steroids or
D-penicillamine, or both, if taken, were not changed during
the study.
Protocol. All patients underwent physical examination, chest radiography, electrocardiography, echocardiography, and pulmonary function testing at baseline. In 9
patients, pulmonary pressure was measured via a SwanGanz catheter; patients with a mean pulmonary pressure
higher than 20 mm Hg were classified as having pulmonary
hypertension (12). Cardiac output values were measured by
the thermodilution technique (13), and the total pulmonary,
total systemic, and pulmonary vascular resistance values
were calculated using standard methods (14).
Nifedipine, 20 mg, was administered orally. After a
30-minute period, during which the patients were free to
walk around, pulmonary function tests, echocardiography,
and heart rate and blood pressure determinations were
repeated. During the next 4 weeks, the patients took 10 mg
of nifedipine 3 times daily. At the end of this period, the
pulmonary function tests and echocardiogram were repeated, an interval history was taken, and a physical examination was performed on all patients.
Pulmonary function tests. Complete pulmonary function studies were performed using a Chestac 25-50 apparatus
(Chestac, Tokyo, Japan). The studies included forced expiratory spirometric measurements, lung volume determination, and measurement of single-breath carbon monoxide
1635
diffusing capacity. Lung volumes were not determined after
the single 20-mg dose of nifedipine because of logistic
reasons. Forced vital capacity (FVC) ( 1 9 , total lung capacity (TLC) (15), and DLco (16) values were considered
normal when they were >80% of predicted. The ratio of
forced expiratory volume in 1 second (FEV,) to FVC was
considered normal when it was >70%. The tests were
conducted in accordance with standard protocols by the
same technician for all patients, at the same time of day, and
at the same environmental temperature of 2625°C. All
values are expressed as a percentage of normal predicted
values, based on reference values for the patient’s age, sex,
and height (l5,16). The mean of at least 2 determinations is
presented for all measurements (17).
The 21 patients were grouped into 4 categories:
normal pulmonary function pattern (FVC, TLC, and DLco
values >80% of predicted), isolated gas-transfer defect,
restrictive ventilatory defect, or obstructive ventilatory defect. An isolated gas-transfer defect was defined as an
isolated reduction in DLco. A restrictive ventilatory defect
was defined as a reduction in TLC, with a normal FEV,/FVC
ratio, and an obstructive defect was defined as a reduction in
the FEVJFVC ratio, irrespective of other values.
Statistical analysis. Statistical comparisons were
made using the t-test for either paired or unpaired variables
when appropriate, along with the necessary compensations
for repeated tests. The correlation coefficient was used to
quantify the relationship between the changes in DLco and
the changes in heart rate and blood pressure caused by the
administration of nifedipine. Spearman’s rank correlation
coefficient was used to detect any trend between the individual DLco values at baseline and after the 20-mg single
dose, as well as after the 4-week course, of nifedipine. Data
are expressed as the mean k SD. The level of significance
was P = 0.05.
RESULTS
Clinical findings. Twenty of the 21 systemic
sclerosis patients studied were women. The mean 2
SD age of all patients was 46.7
12.3 years (range
20-64). The mean & SD duration of disease was 7.5 ?
5 years (range 1-22). Twenty patients had Raynaud’s
phenomenon, 12 of whom also had a history of digital
ulcers. Physical examination, chest radiography, electrocardiography, and echocardiography showed no
evidence of cardiac disease or pulmonary hypertension in any of the 21 patients; however, 10 patients
reported mild dyspnea on exertion.
Chest radiography results were normal in 6
patients and showed interstitial markings in 15. Nine
of these 15 patients had reticular pattern on lower lung
fields only, 4 had reticular pattern on both lower and
upper lung fields, and 2 showed reticulonodular pattern and/or honey-combing. All patients had sinus
rhythm on electrocardiographs; however, 4 had infre-
*
SFIKAKIS ET AL
Table 1. Baseline pulmonary function test results in patients with
systemic sclerosis’
FVC
All patients
(n = 21)
Normal pattern
(n = 6)
Restrictive ventilatory
defect
(n = 8)
Isolated gas-transfer
defect
(n = 7)
FEV ,/
FVC
89221 8 4 2 8
TLC
DLco
88216 68522
106
2
16 86
2
7 102
f
16 95
72
2
12 87
2
8
f4
93
2
17 81 2 9
* 9t
49
f
16
98 2 14 66
2
10
73
* Values are the mean rt SD percentage of predicted values, except
for the forced expiratory volume in I second/forced vital capacity
ratio (FEVJFVC), which is the mean t SD percentage. TLC = total
lung capacity: DLco = carbon monoxide diffusing capacity.
t P = 0.00003 versus patients with restrictive ventilatory defect and
P = 0.0003 versus patients with isolated gas-transfer defect.
quent ventricular ectopic beats. Heart rate ranged
from 70 beatdminute to 100 beatdminute (mean -+ SD
78 ? 9). The mean arterial blood pressure ranged from
80 mm Hg to 118 mm Hg (mean ? SD 101 ? 12).
Hemodynamic findings. All 9 patients who underwent right heart catheterization had normal cardiac
output values (mean ? SD 5.8 ? 0.6 literslminute) and
normal total systemic resistance values (mean SD
1,268 2 255 dynes.se~.cm-~).
The mean pulmonary
pressure ranged from 8 mm Hg to 17 mm Hg (mean 2
SD 12.2 -+ 2.9). Total pulmonary resistance values
ranged from 113 to 245 dynes.sec.crn-’ (mean ? SD
169 2 43). Pulmonary vascular resistance values were
78, 98, 102, 103, 106, 121, 130, 141, and 187
dynes.sec.cm-’ (mean 2 SD 118 2 32), respectively
(upper limit of normal in our laboratory 120
dynes.sec.cm-.’).
Pulmonary function test results. Table 1 shows
the mean 2 SD baseline values for FVC, FEV,/FVC,
TLC, and DLco in the 21 patients studied. Six patients
(29%) had normal pattern, while the remaining 15
patients (71%) had reduced DLco levels. Eight of
these 15 patients showed a restrictive ventilatory
defect, and 7 showed an isolated gas-transfer defect.
None of our patients had an obstructive ventilatory
defect. DLco levels were significantly higher in the
normal pattern group compared with the restrictive
ventilatory defect (P = 0.00003) and isolated gastransfer defect groups (P= 0.0003). Comparison of the
latter 2 groups revealed lower DLco levels in those
with restrictive ventilatory defect, but the difference
did not reach significance (P = 0.08).
*
Effects of nifedipine. Each patient’s baseline
values were compared with those obtained after the
initial 20-mg dose of nifedipine, as well as after the
4-week course of nifedipine (Table 2). The single dose
of nifedipine did not significantly change either the
FVC or the FEVJFVC values, but the DLco values
increased by 13% (P = 0.01), heart rate increased by
8% (P= 0.0002), and mean arterial pressure decreased
by 9% (P = 0.002). After 4 weeks of nifedipine
therapy, the only values that changed significantly
from baseline were the DLco (increased by 18%;P =
0.006) and the mean arterial pressure (decreased by
9%; P = 0.0004) (Table 2). There was no correlation
between the increase in DLco and either the decrease
in blood pressure or the increase in heart rate after the
initial dose of nifedipine (rl) or after the 4-week course
(r,). The correlation coefficient between DLco
changes and mean arterial pressure changes (rl =
0.357, r, = -0.183), as well as between DLco changes
and heart rate changes (r, = -0.064, r, = -0.037). was
not significant at any level.
Nifedipine had a much more pronounced effect
in patients with isolated or restrictive defects, than in
patients with normal pulmonary function pattern (Table 3). DLco levels increased by a mean of 16%
immediately after the single oral dose of nifedipine and
by a mean of 25% after the 4-week course of nifedipine
in the 15 patients with isolated or restrictive ventilatory defect. However, DLco changes were not significant (+4% and + l % , respectively) in the 6 patients
with normal pulmonary function pattern (Table 3). In
Table 2. Pulmonary function test values, heart rate, and mean
arterial pressure before and after nifedipine therapy in patients with
systemic sclerosis*
Baseline
FVC
FEVJFVC x 100
TLC
DLco
Heart rate (beats/minute)
Mean arterial pressure
(mm Hg)
89
84
88
68
78
f
f
21
8
f 16
2 22
f9
101 f 12
After a 20-mg
dose of
nifedipine
88 2 20
83 f 8
-
74
84
92
f
-t
f
20t
81
137
After 4
weeks of
nifedipine
89
84
89
76
79
91
2
2
2
2
2
2
19
7
16
17$
8
13#
* Values are the mean 5 SD; pulmonary function test values are the
mean f SD percentage of predicted values. See Table 1 for
explanations of abbreviations.
t P = 0.01 versus baseline, by paired r-test.
$ P = 0.006 versus baseline, by paired r-test.
1P < 0.0002 versus baseline, by paired i-test.
7 P = 0.002 versus baseline, by paired r-test.
# P = O.ooo4 versus baseline, by paired r-test.
NIFEDIPINE IN SYSTEMIC SCLEROSIS
Table 3. Carbon monoxide diffusing capacity before and after
nifedipine therapy in patients with systemic sclerosis, categorized
according to pulmonary function*
~~~
~~
~~
After a 20-mg
dose of
Baseline nifedipine
Isolated gas-transfer defect
or restrictive defect
(n = 15)
57 2 IS
Normal pattern
9529
(n = 6)
64 2 14t
9927
~
After 4
weeks of
nifedipine
68 f 12$
96 C 9
* Values are the mean 2 SD percentage of predicted values.
t P = 0.02 versus baseline, by paired t-test.
j:
P = 0.004 versus baseline, by paired I-test.
patients with restrictive ventilatory defect, compared
with patients with isolated gas-transfer defect, there
were higher mean percentage increases in DLco both
immediately after the single oral dose (+20% versus
+ 12%) and after 4 weeks (+37% versus + 11%); however, the comparisons between patient groups revealed no significant differences.
Spearman’s rank correlation coefficient revealed a linear trend between individual baseline
DLco levels and changes in DLco levels after a single
oral dose of nifedipine (r = -0.6034, P = 0.02), as well
as between individual baseline DLco levels and
changes in DLco levels after 4 weeks of nifedipine
treatment (r = -0.6362, P = 0.01). Thus, the lower the
DLco value at baseline, the higher the increase caused
by nifedipine.
Analysis of the echocardiograms revealed no
significant differences in diastolic and systolic dimensions or in the ejection fraction of the left ventricle,
either immediately after the 20-mg dose or after the
4-week course of nifedipine.
Nifedipine was well tolerated by all patients.
Although 4 patients reported mild flushing or headache
during the first days of long-term administration, neither specific treatment of these symptoms nor modification of the protocol was required.
DISCUSSION
Pulmonary involvement is a common feature of
systemic sclerosis (1,2,18) and has been associated
with reduced survival (19). No treatment has been
considered uniformly effective (3). The lack of correlation between the severity of pulmonary vascular
disease and interstitial fibrosis is well documented
(20-22). The initial emphasis on fibrosis being the
1637
primary event, with gradual obliteration of the vascular
bed as a consequence, has recently shifted toward consideration of the general vascular system as the main
abnormality, with the changes in the lungs being equivalent to changes in other affected organs (5,18-23).
This study demonstrates that nifedipine, a drug
that is a well-established treatment for Raynaud’s
phenomenon (8,9), significantly improves diffusing capacity of the lung in patients with systemic sclerosis
and lung involvement. We found impaired diffusing
capacity in 70% of our patients; DLco was the most
frequent abnormal finding on pulmonary function
tests. These data are consistent with the findings
reported in the majority of the literature (I ,2,18).
Administration of nifedipine did not significantly
change any of the pulmonary function findings, either
after the single dose or after 4 weeks of therapy, except
for the DLco levels. This change did not correlate with
changes in heart rate and blood pressure.
These findings are compatible with clinical observations suggesting abnormal vasoconstriction in the
pulmonary vasculature of patients with systemic sclerosis (4,18,23-27). Furst et a1 demonstrated a decrease
in pulmonary perfusion in 5 of 9 patients with systemic
sclerosis after induction of peripheral Raynaud’s phenomenon (23). Naslund et a1 described a patient with
systemic sclerosis in whom either environmental exposure to cold or infusion of iced saline into the
pulmonary artery led to an elevation in pulmonary
artery pressure, suggesting the occurrence of pulmonary vasoconstriction (24). However, Shuck et a1
found no significant change in pulmonary artery pressure during peripheral Raynaud’s phenomenon induced
in 9 scleroderma patients (25). Wise et al demonstrated
that the normal response to cold pressor stimulus was an
increase in the DLco levels, which results from the
redistribution of blood from the peripheral circulation to
the pulmonary circulation (26). Patients with systemic
sclerosis had no such increase in DLco levels with cold
pressor stimulus, which suggests that there is an altered
pulmonary vascular response due to either structural or
functional abnormalities of the pulmonary vascular bed.
McCarthy et a1 demonstrated a significant decrease in
pulmonary ditrusing capacity in 7 patients with systemic
sclerosis, compared with 8 controls, after breathing cold
air (18).
Diffusing capacity reduction has been thought
to be the earliest detectable abnormality in the pulmonary involvement of systemic sclerosis (28). A severely depressed DLco level is an important predictor
SFIKAKIS ET AL
1638
of mortality in scleroderma patients (29), and if it is
lower than 43% of predicted, it has the greatest sensitivity of any single diagnostic test in detecting definite
pulmonary hypertension (30). Ungerer et al suggest
that a reduction in single-breath DLco reflects extensive destruction of the pulmonary capillary bed, which
will lead to an increase in pulmonary vascular resistance and a resultant pulmonary hypertension (30).
The pathogenetic mechanism of DLco reduction in
pulmonary vasculopathies in general seems to be a
combination of decreased blood volume in the pulmonary capillaries and deterioration of ventilation/
perfusion matching, due to alterations in the area and
thickness of the blood-gas barrier (31). In contrast,
increased blood volume in the pulmonary capillaries
augments the DLco; this augmentation is observed
during exercise in normal subjects, as well as in
patients who are in a supine position compared with
those in a standing position (31).
Recently, we evaluated the hemodynamics of
20 patients with systemic sclerosis, before and after
administration of nifedipine and captopril. Although
these patients had no clinical evidence of cardiac
disease or pulmonary hypertension, and despite the
demonstration of normal pulmonary pressure (confirmed by catheterization in 17 of them), 10 patients
were found to have high pulmonary vascular resistance, which was reversed to normal levels with
nifedipine but not with captopril (unpublished observations). Together, these results provide evidence that
nifedipine improved DLco levels by reducing pulmonary vascular resistance and subsequently increasing
pulmonary capillary blood volume. The DLco levels
improved by 16% immediately after treatment and by
25% after 4 weeks of therapy in the 15 scleroderma
patients with lung involvement. In contrast, DLco
levels remained unchanged in the 6 patients who had
normal pulmonary function test results, as well as in 5
healthy volunteers who had been tested under the
same conditions. The patients’ response is probably
due to the coexistence of an active vasoconstrictive
element and fixed structural damage in the cardiopulmonary vasculature, which is reversible by nifedipine.
One limitation of our study is that we did not
test gas exchange before and after nifedipine administration. Although the measurement of gas exchange at
rest is the least sensitive monitor of parenchymal
changes in interstitial disorders (32), we measured
resting arterial Po, levels in a number of patients. All
values were within normal ranges, and because the
procedure was quite stressful to the patients, we
decided not to include it in the protocol of this study.
In summary, in our study of 21 patients with
systemic sclerosis who had no evidence of cardiac
disease or pulmonary hypertension, 15 were found to
have impaired diffusing capacity of the lung, which
improved significantly immediately after oral administration of a single 20-mg dose of nifedipine. This
improvement continued after 4 weeks of treatment
with nifedipine. These findings suggest that these
patients have a vascular lesion that includes reversible
vasoconstriction in the pulmonary vascular bed. Perhaps, reversal of vasospasm might interrupt or delay
the development of fixed pulmonary vascular changes;
thus, the administration of nifedipine therapeutically
or prophylactically against pulmonary vascular damage should be further assessed. A double-blind controlled study of nifedipine therapy for pulmonary
disease in systemic sclerosis is warranted. However, it
should be a long-term trial, and it should include
assessments of disease progression and subsequent
outcome, rather than just an improvement in DLco.
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