(Circulation. 2000;101:2066.)
© 2000 American Heart Association, Inc.
Clinical Investigation and Reports |
Improvement in Exercise Capacity With Nitric Oxide Inhalation in Patients With Precapillary Pulmonary Hypertension
From the Division of Cardiology and Pulmonary Circulation, Department of Medicine, National Cardiovascular Center, and Division of Circulatory Dynamics, National Cardiovascular Research Institute (A.S.), Suita, Osaka, Japan.
Correspondence to Toru Satoh, MD, Cardiopulmonary Division, Department of Medicine, Keio University School of Medicine, Shinanomachi 35, Shinjukuku, Tokyo 160-8582, Japan. E-mail tsatoh{at}cpnet.med.keio.ac.jp
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Abstract |
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Background—Patients with precapillary pulmonary hypertension (PH) exhibit a poor exercise capacity due to an impaired vasodilatory response of their pulmonary arteries. By causing the pulmonary artery to dilate, inhaled nitric oxide (NO) may allow an increase in exercise capacity in patients with PH.
Methods and Results—On 2 separate days, 3 days apart, 14 patients
with precapillary PH (10 primary PH, 4 residual PH after correction of
an intracardiac shunt; age, 40±12 years; mean pulmonary artery
pressure, 60±23 mm Hg) performed exercise, with and without
inhalation of 20 ppm NO, on a cycle ergometer. The work rate was
increased 15 W/min until their symptom-limited maximum, with
breath-by-breath gas analysis. Patients were randomly and
blindly selected to inhale NO on either their first or second test.
Peak exercise load and anaerobic threshold tended to
increase, but not significantly. Peak oxygen consumption
(
O2) and
O2/W ratio increased
significantly, by 18% and 22%, respectively (peak
O2, 13.6±3.6 to 16.0±4.1 mL ·
kg-1 · min-1;
O2/W ratio, 5.8±2.4 to 7.1±2.3
mL · kg-1 · min-1 ·
W-1; both P<0.01). Peak
O2 increased >10% in 12 of the 14
patients. However, respiratory quotient at peak exercise decreased from
1.22±0.15 to 1.09±0.15 (P<0.01).
Conclusions—Inhaled NO substantially increases oxygen consumption at the same workload during exercise. This finding supports the possibility of ambulatory NO inhalation therapy in patients with precapillary PH.
Key Words: nitric oxide • exercise • pulmonary heart disease • hypertension
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Introduction |
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The normal pulmonary circulation can accommodate an increase in blood flow during exercise with a minimal rise in pulmonary pressure. It can even allow a 50% decrease in pulmonary vascular resistance during heavy exercise through passive pulmonary vascular dilatation and recruitment.1 Patients with moderate precapillary pulmonary hypertension show a reduction in pulmonary vascular resistance of only 20%, and those with severe pulmonary hypertension with pulmonary vascular resistance of, say, >10 Wood units even show an increase in resistance2 due to a reduction in the pulmonary arterial bed for vessel recruitment and poor pulmonary vasodilatory capacity during exercise. Vasodilator agents have been used to treat these patients3 4 and may facilitate pulmonary artery dilatation and cause an increase in aerobic capacity during exercise.
Palmer et al5 reported in 1987 that nitric oxide (NO) is an endothelium-derived relaxing factor that dilates the pulmonary artery through the production of cGMP. Since then, NO has been used as a vasodilator agent for newborn infants with persistent pulmonary hypertension6 7 and patients with pulmonary hypertension associated with congenital heart disease8 as well as those with adult respiratory distress syndrome.9 It has been reported that NO inhalation improves exercise capacity in patients with left ventricular dysfunction and postcapillary pulmonary hypertension.10 11 However, there have been no reports concerning patients with precapillary pulmonary hypertension, although Channick et al12 reported that simple nasal delivery of inhaled NO at home improves pulmonary hypertension and the quality of life in patients with primary pulmonary hypertension.
Accordingly, the purpose of this study was to examine whether inhaled NO, a potent pulmonary artery dilator, is able to improve the exercise capacity on a cycle ergometer in patients with precapillary pulmonary hypertension, including primary pulmonary hypertension and residual pulmonary hypertension after surgical correction of an intracardiac shunt.
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Methods |
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Patients
The study subjects were 14 patients with precapillary pulmonary hypertension (4 men and 10 women; age, 40±12 years, ranging from 25 to 59 years; mean pulmonary artery pressure, 60±23 mm Hg; pulmonary vascular resistance, 16.1±9.8 Wood units; cardiac output, 4.2±1.9 L/min; mean right atrial pressure, 7.9±4.2 mm Hg; mean pulmonary capillary wedge pressure, 5.1±2.0 mm Hg). There were 10 patients with primary pulmonary hypertension and 4 with residual pulmonary hypertension after correction of an intracardiac shunt (3 atrial septal defect, 1 ventricular septal defect). Primary pulmonary hypertension was defined as pulmonary hypertension unexplained by any secondary cause, based on the National Institute of Health Registry criteria for primary pulmonary hypertension.13 A residual shunt could not be identified by cardiac ultrasonography in patients with pulmonary hypertension after correction of an intracardiac shunt. In these patients, mild to moderate precapillary pulmonary hypertension had been noted before surgery, which slowly worsened after the surgery. Patients who had additional left ventricular dysfunction and resultant postcapillary pulmonary hypertension were excluded. All patients had symptomatic right heart failure (2 patients were in New York Heart Association functional class II and 12 patients in class III) but were in a stable condition during hemodynamic and exercise tests. Hemodynamic parameters were obtained by means of right heart catheterization within 2 weeks after the exercise tests. Pulmonary hypertension was defined as a mean pulmonary artery pressure of >25 mm Hg. Arterial PO2 and PCO2 were 67±12 and 33±5 mm Hg, respectively. Eleven of the 14 patients studied received ambulatory oxygen therapy. All subjects gave informed consent in writing, and this study was approved by the Ethical Committee of the National Cardiovascular Center (No. 10-1).
Exercise Protocol
The patients performed exercise seated on a cycle ergometer.
They first pedaled at 55 rpm without any added load for 1 minute. The
work rate was then increased by 15 W/min up to their symptom-limited
maximum. Breath-by-breath gas analysis was performed with an
AE280 gas analyzer (Minato Medical Science) connected to
a personal computer running analyzing software. Peak oxygen uptake was
determined as the value of averaged data during the final 15 seconds of
exercise. The ratio of change in oxygen uptake to change in work rate
(O2/W ratio) was
calculated as the slope of oxygen consumption per unit workload from 1
minute after the start of load addition until 85% maximal
O2. The exercise tests were
performed on 2 separate days, 3 days apart, with and without inhalation
of 20 ppm NO. Patients were randomly and blindly selected to inhale NO
on either their first or second test. Patients first selected for NO
inhalation were not different from those who received it on the second
test. NO inhalation was started 2 minutes before the start of exercise
when resting respiratory measurement was commenced. Blood pressure was
measured at the brachial artery with a sphygmomanometer. The
E-CO2
slope, a parameter indicating the degree of dead-space
ventilation, was determined as the linear regression slope of the
E and CO2
relation from the start of exercise until the RC point (the time up
until which ventilation is stimulated by CO2
output and end-tidal CO2 tension begins to
decrease). The appearance of the
O2 plateau at maximal exercise
was defined as (1) an invariant or <50-mL/min change in
O2 lasting at least 30 seconds
with an increment in workload according to breath-by-breath
analysis or (2) a rapid increment in E
despite O2
decrement.14
NO Inhalation
Figure 1
shows the NO delivery
system. NO (800 ppm) (Kyoto Sanso Medical) was mixed with compressed
air in an NO gas blender (NO-10, Taiyo Toyo Sanso Co Ltd) to obtain 20
ppm NO. The compressed air had the same composition as ambient air, and
the volume of compressed air was manually altered according to the
minute ventilation during exercise. NO concentration was monitored by
an NO/NO2 analyzer (NOA-7000, Shimadzu Co
Ltd) and manually brought to a concentration of 20 ppm by fine
adjustment of the NO volume being introduced into the NO blender.
Because the inspired NO was supplied from a cylinder with a high
concentration of 800 ppm NO and constituted only a small fraction of
the total inspired gas, inspired oxygen concentration was influenced
very little. Inspired NO mixed with compressed air was stored for a
short time in a 50-L reservoir bag. The inspired concentration of
NO2 was negligible, being <1 ppm.
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Statistical Analysis
All data are expressed as mean±SD. Comparison between
variables with and without NO inhalation in the resting state and
at peak exercise was performed by paired t test. Comparison
of the number of patients with a
O2 plateau between
with and without NO inhalation was performed by
2 analysis. Linear regression
analysis was used to correlate the hemodynamic
variables with the percent peak
O2 change. A value
of P<0.05 was considered statistically significant.
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Results |
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Heart rate, systolic and diastolic blood pressures, and oxygen consumption before exercise and at peak exercise were not different between with NO inhalation and without NO inhalation (Table
). Peak exercise load and
anaerobic threshold (AT) did not change significantly with
NO inhalation but tended to increase (peak exercise load, 75±21
increasing to 80±21 W; AT, 9.1±1.8 to 9.7±1.9 mL ·
kg-1 · min-1;
P=NS). Nine of the 14 patients showed an increase in AT.
Peak oxygen consumption and
O2/W ratio,
where W is work rate, increased significantly (18% and 22%,
respectively, P<0.01 for both variables) after NO
inhalation, although the respiratory quotient (index of exercise
effort) decreased from 1.22±0.15 to 1.09±0.15 (P<0.01),
which indicates increased oxygen consumption with less effort. Twelve
of the 14 patients demonstrated an increase in peak
O2 of 
10% (Figure 2). A
O2 plateau at peak
exercise, indicating that exercise had been terminated by certain
circulatory limitation,14 appeared in 11
patients, but this number was reduced to 5 by NO inhalation. The
significant decrease (P=0.03) in the number of patients with
circulatory limitation after NO inhalation during exercise implies that
NO may improve pulmonary flow. These observations suggest that
the hemodynamic improvements may have brought about a
significant increase in peak oxygen consumption. The slope of
E-CO2,
an indicator of dead-space ventilation, was not significantly different
between with NO inhalation and without NO inhalation (43.0±12.3 and
42.6±10.4, respectively).
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Mean pulmonary arterial pressure, pulmonary
vascular resistance, cardiac output, and mean right atrial pressure did
not correlate with the percent increase in peak
O2 with NO inhalation (Figure 3).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The present study showed that NO inhalation significantly increased oxygen consumption at the same workload during exercise in patients with precapillary pulmonary hypertension. The improvement due to NO inhalation may be ascribed to pulmonary arterial dilatation with increased cardiac output, judging from the concomitant increase in
O2/W ratio and the
decrease in cases with a O2
plateau at peak exercise. The improvement in oxygen consumption at the
same workload during exercise with NO inhalation did not correlate with
the magnitude of hemodynamic abnormalities.
Effects of NO Inhalation During Exercise
Because of impaired pulmonary dilatation during exercise,
pulmonary vascular resistance does not decrease in patients
with precapillary pulmonary hypertension, whereas it decreases
in normal subjects. NO inhalation is a unique form of treatment that
uses selective pulmonary arterial dilatation,
because it dilates the pulmonary arteries corresponding to the
ventilated alveoli without affecting systemic
arteries.15 16 Riley et al17 reported that
during exercise, intrinsic NO production, as measured from the
exhaled NO, failed to increase in patients with primary
pulmonary hypertension. Likewise, it failed to increase in
those with pulmonary fibrosis, whereas it increased in normal
subjects. This lack of increase results in pulmonary
endothelial dysfunction and impaired recruitment of the
pulmonary vasculature during exercise. Thus, treatment with NO,
as a selective pulmonary vasoreactive agent, can improve
pulmonary arterial dilatation and thus increases
cardiac output to bring about a resultant increment in peak oxygen
consumption.
Matsumoto et al10 reported that NO inhalation improved the
exercise capacity in 8 patients with left ventricular
dysfunction and postcapillary pulmonary hypertension by
alleviating both pulmonary hypertension and
ventilation-perfusion mismatch. According to Koelling et
al,11 after inhalation of 40 ppm NO, peak
O2 increased in 8 of 14
patients with severe left ventricular failure and right
ventricular dysfunction, with a mean increase of 3.4%. Our
first report of an acute improvement in exercise capacity with NO
inhalation in patients with precapillary pulmonary hypertension
demonstrated that 86% of the patients showed an increase in oxygen
consumption of >10% at the same workload during exercise for less
effort, as represented by a lower peak respiratory
quotient. From these results, we postulate that patients with
precapillary pulmonary hypertension can benefit from NO
inhalation during exercise.
In the present study, NO inhalation increased peak
O2 and
O2/W ratio
significantly. The O2/W
ratio indicates oxygen transport per unit workload to the exercising
legs and is an index of circulatory capability.18 In this
patient population, an acute change in
O2/W ratio was
considered to reflect change in cardiac output rather than other
circulatory changes through pulmonary arterial
dilatation with NO inhalation. A
O2 plateau at peak exercise,
indicating that exercise had been terminated by certain circulatory
limitations,14 appeared in 11 patients, but this number
decreased to 5 as a result of NO inhalation. In patients with
precapillary pulmonary hypertension, failure of cardiac output
to increase because of impaired pulmonary vasodilation is the
most likely circulatory limitation. The significant decrease in the
number of patients with circulatory limitation after NO inhalation
during exercise suggests that NO may improve pulmonary flow.
These results suggest that with NO inhalation, the increase in cardiac
output may contribute to an increase in peak
O2. The possible cardiac
output increase can be explained by dilatation of pulmonary
arteries. In addition, pulmonary hypertension and the resultant
right ventricular pressure overload cause left
ventricular diastolic
dysfunction.19 20 NO dilates the pulmonary
arteries, reduces right ventricular afterload, and improves
left ventricular diastolic function, resulting
in an increase in peak oxygen consumption during exercise.
Peak exercise load, AT, and the symptoms at peak exercise did not
improve. Peak exercise load might have been increased intentionally by
the examiner because he could not be blinded to whether NO was inhaled
or not, because the examiner needed to perform meticulous adjustment of
NO concentration and attend to the NO oxidant product. The fact
that the respiratory quotient was decreased at peak exercise with NO
inhalation means that the patients made less effort. They could have
increased their workload if they had made more effort at the same level
of respiratory quotient. This was confirmed by the finding that without
NO inhalation, 11 of 14 patients finished their exercise in association
with a O2 plateau, indicating
circulatory limitation, and with NO inhalation, only 5 patients
demonstrated this phenomenon, but the remaining 6 patients did not show
a O2 plateau, and their
exercise was limited by leg fatigue at the same workload. AT showed a
tendency to improve (P=0.06), but the increase was not
significant, partly because AT is influenced by muscle
energetics,21 which are not improved immediately. The
symptoms at peak exercise also did not improve, partly because the
symptoms were determined after each exercise test with and without NO
inhalation and were not compared with each other, and partly because
the symptoms of leg fatigue and dyspnea are generally difficult for
patients to differentiate.22
The degree of increase in exercise capacity did not correlate with the
resting hemodynamics, which suggests that NO reactivity
might be related to some factors other than pulmonary artery
rigidity, such as sensitivity to cGMP activity.23 Koelling
et al11 argued that patients with elevated
pulmonary pressure whose mean pulmonary pressure is
<60 mm Hg and moderately high benefit with respect to exercise
capacity from NO inhalation. In our study, peak
O2 increased until it reached
a mean pulmonary arterial pressure of 60
mm Hg and then declined.
Side Effects of NO
Because NO is a potentially poisonous gas, side effects had to be
carefully monitored. NO was mixed with air and stored in a reservoir
bag for a few seconds, which would have produced the highly harmful
oxidation product NO2.
NO2 was therefore measured before inhalation, but
the level was found to be acceptable at a negligible concentration. The
concentration of methemoglobin, another noxious product resulting
from NO entering the blood, was <1%.
Clinical Implications
The short-term beneficial effects of inhaled NO on oxygen
consumption support the possibility of long-term, home-based,
ambulatory NO inhalation therapy. Kouyoumdjian et al24
reported that continuous inhalation of NO induced sustained
pulmonary vasodilatation and pulmonary vascular
remodeling in chronically hypoxic rats, which suggests that continuous
inhalation may prevent the progression of thickening of the
pulmonary vasculature in patients with pulmonary
hypertension. If long-term NO inhalation has few side effects and is
economically affordable, this therapy will be introduced more often and
may improve the quality of life and even the prognosis in patients with
precapillary pulmonary hypertension.
Received September 9, 1999; revision received November 30, 1999; accepted December 10, 1999.
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