(Chest. 2001;119:970-973.)
© 2001
American College of Chest Physicians
One-Year Continuous Inhaled Nitric Oxide for Primary Pulmonary Hypertension*
Gregorio Pérez-Peñate, MD;
Gabriel Julià-Serdà, MD;
Juan María Pulido-Duque, MD;
Elias Górriz-Gómez, MD and
Pedro Cabrera-Navarro, MD
*
From the Services of Pneumology (Drs. Pérez-Peñate, Julià-Serdà, and Cabrera-Navarro) and Vascular Radiology (Drs. Pulido-Duque and Górriz-Gómez), Hospital General de Gran Canaria "Dr. Negrín," Las Palmas de Gran Canaria, Spain.
Correspondence to: Gregorio Pérez-Peñate, MD, Servicio de Neumología, Hospital General de Gran Canaria "Dr. Negrín," Barranco de la Ballena s/n, E-35020 Las Palmas de Gran Canaria, Spain; e-mail: gperez{at}correo.hpino.rcanaria.es
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Abstract
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We describe a case of long-term administration of nitric oxide (NO) in a
32-year-old man who was admitted with exertional dyspnea and anasarca.
A diagnosis of primary pulmonary hypertension was made. An acute
vasodilator trial with inhaled NO showed a 5% reduction of the mean
pulmonary artery pressure. Long-term NO inhalation therapy was
initiated. Twenty days later, the dyspnea improved, the anasarca
resolved, and the PaO2 level increased. After
12 months of NO therapy, the patient remained stable and no signs of
toxicity or tachyphylaxis were observed. To our knowledge, this is the
first report of 1 year of continuously inhaled NO in an adult patient
with primary pulmonary hypertension. These findings suggest that
prolonged NO therapy might be an effective alternative, at a lower
cost, to the continuous IV infusion of
epoprostenol.
Key Words: nitric oxide • primary pulmonary hypertension • pulmonary vasodilator
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Introduction
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Nitric
oxide (NO) is a potent pulmonary vasodilator
produced in vivo by the endothelium via the metabolism of
L-arginine in the presence of NO synthetase. Systemic hypotension is
avoided when NO reaches the bloodstream, and it is rapidly inactivated
by hemoglobin, forming nitrates. NO also inhibits the proliferation of
vascular smooth muscle and alters the gene expression of growth
factors, vasoconstrictors, and endothelial cell adhesion
molecules.1
2
Inhaled NO has been used in the treatment of
persistent pulmonary hypertension of the newborn,3
primary
pulmonary hypertension,4
5
ARDS,6
and
postoperative graft dysfunction after lung and heart
transplantation.7
At the later stages of primary or
secondary pulmonary hypertension, inhaled NO might offer a promising
alternative treatment. We used NO, 80 ppm, for as long as 12 months to
treat a patient with severe primary pulmonary hypertension.
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Case Report
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A 32-year-old man, who was an ex-addict of inhaled heroin, was
admitted to the hospital with a 2-year history of dyspnea and anasarca
(New York Heart Association functional class IV). Physical examination
showed a systolic murmur in the pulmonary area and generalized
edema. The results of laboratory tests were normal except for a
creatinine clearance of 59 mL/min/1.73 m2.
The results of an arterial blood gas test carried out while the patient
was breathing room air, and other respiratory tests are summarized in
Table 1
. On the basis of the findings of serologic tests, chest roentgenograms,
chest CT scans, pulmonary Doppler arteriography and Doppler
echocardiography, a diagnosis of primary pulmonary hypertension was
made. The patient was treated with warfarin, digoxin, spironolactone,
high-flow supplemental oxygen, and nifedipine. Because of a small
improvement in the clinical symptoms, nifedipine therapy was
discontinued. The patient underwent right heart catheterization
(triple-lumen pulmonary artery catheter, model SP 5107H; Abbott
Laboratories; Maidenhead, UK) followed by an acute vasodilator
trial with 80-ppm inhaled NO for 15 min. NO mixed with
N2 in a concentration of 800 ppm (Carburos
Metálicos, SA; Barcelona, Spain) was blended with air in a
Douglas bag. The subject, wearing a nose clip, breathed the
NO-N2/air mixture through a mouthpiece connected
to a one-way valve (Hans-Rudolph; Kansas City, MO). Recordings were
made of the ECG (Minimon 7132; Kontrom Instruments; Watford,
UK), oxyhemoglobin level (Bio 3740; Datex-Ohmeda; Miami, FL),
inspiratory concentration of NO and NO2 (Printer
Nox; Micro Medical; Rochester, UK), and fraction of inspired
oxygen (MaxO2 Oxygen Analyzer OM25-A; Ceramatec;
Pau, France).
A 5% reduction of mean pulmonary artery pressure and a 23%
reduction in calculated pulmonary vascular resistance accompanied by a
21% increase in cardiac output was noted after the completion of the
short-term trial. Informed consent was obtained from the patient and
from the ethics committee of the hospital to initiate continuous NO
inhalation therapy. A tank of NO mixed with N2 in a
concentration of 800 ppm was connected to an oxygen-demand valve
(Demand-flow-62; Air Products and Chemicals; Allentown, PA) and
administered to the patient through a nasal cannula at the beginning of
the inspiratory cycle. The system is activated on demand at -1.5 cm
H2O inspiratory pressure. To produce an inspired
NO concentration of 80 ppm for the patient’s baseline minute volume of
8 L, the NO-N2/air mixture flow was 0.9 L/min.
Twenty days later, there was an improvement in dyspnea, renal function
(creatinine clearance, 92 mL/min/1.73 m2), edema,
and gas exchange while breathing room air
(PaO2, 65 mm Hg;
PaCO2, 34 mm Hg). The patient
continued inhaled NO therapy at home using a tank 7.5
m3 in size. A portable aluminum tank of 1
m3 was supplied for ambulation. No complications
or adverse effects were noted, and the concentrations of NO and
NO2 measured at the patient’s home were
negligible. After 12 months of NO therapy, the patient was in New York
Heart Association functional class II, with no edema, and his baseline
PaO2 level was 70 mm Hg. A 9%
reduction of mean pulmonary artery pressure was demonstrated. Results
of the first and second right heart catheterization are shown in Table 2
.
View this table:
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Table 2.. Hemodynamic Data at Baseline, During Acute
Vasodilator Trial and After 1 Year of Continuous Inhaled NO Therapy
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Discussion
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Primary pulmonary hypertension is a disease that involves
the small pulmonary arteries, which exhibit intimal proliferation and
fibrosis, medial hypertrophy, and thrombosis.
Treatment of the disease is based on therapy with anticoagulation and
vasodilator agents, such as calcium-channel blockers and
epoprostenol.8
Long-term infusion of epoprostenol improves
clinical symptoms, hemodynamic characteristics, and survival of
pulmonary hypertensive patients.8
Tolerance of
epoprostenol with long-term treatment can only be overcome by
continuing to increase the dosage over time. In addition, major adverse
effects of long-term therapy are attributable to the complexity and
expense of the delivery system including pump malfunction,
catheter-related infections, and thrombosis.8
9
10
11
Clinical and hemodynamic beneficial effects of long-term NO inhalation
therapy in patients with severe primary pulmonary hypertension have
been reported in the literature.4
5
In the case
presented here, continuous inhalation of NO resulted in a rapid
clinical and gasometric improvement that was maintained over the course
of a 1-year follow-up period. After 12 months of inhaled NO therapy,
gas exchange was more efficient and mean pulmonary artery pressure
showed a greater decrease than that observed in the initial vasodilator
trial. In accordance with other reports,4
5
these findings
suggest that the inhalation of NO has a similar efficacy to therapy
with epoprostenol in patients with severe pulmonary hypertension. In
contrast to therapy with IV epoprostenol, inhalation of NO
decreased pulmonary vascular resistancewithout affecting systemic
vascular resistance. Other advantages include the avoidance of
catheter-related infections and lower cost.
NO inhalation therapy remains promising, but the following several
important areas remain to be studied: the potential toxicity of inhaled
NO; the duration of treatment; and the determination of safe levels of
NO exposure for the lung. The safety of continuous long-term NO
inhalation has not been established definitely. A possible problem is
the remarkable increase in pulmonary resistance after the interruption
of NO inhalation, which has been reported in pulmonary
hypertension of the newborn and in patients with ARDS.11
Inhaling NO at high levels may cause marked methemoglobinemia, but the
inhalation of NO at low levels seems to be safe. Although high levels
of NO may cause pulmonary edema and death, the lack of lung
parenchymal abnormalities shown by electron microscopy in patients who
have undergone lung transplants suggests that there is no significant
tissue toxicity. No signs of NO toxicity or tachyphylaxis were
detected in our patients with the dosage used. In addition, the
oxygen-demand valve in the ambulatory NO inhalation system allowed the
use of nasal cannulas with minimal contamination of the environment and
negligible concentrations of NO and NO2 measured
at home. The use of a tank of NO mixed with NO2 in a
concentration of 800 ppm was equally as safe as the 80 ppm NO reported
previously by others, and it lasted longer. In patients with
ARDS,12
full pulmonary vasodilation requires a higher
concentration of NO (as much as 100 ppm) when compared with the
concentration (< 10 ppm) required to simply achieve an improvement in
ventilation-perfusion matching. Adatia et al7
have
suggested a dose of 80 ppm NO as a starting point to control severe
pulmonary hypertension.
In summary, as far as we are aware, this is the first report of inhaled
NO therapy over 12 months in an adult patient with severe primary
pulmonary hypertension. This mode of therapy may be an effective
alternative to the continuous IV infusion of epoprostenol, at a lower
cost and with a lower rate of complication.
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Acknowledgements
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The authors thank Carburos Metálicos,
S.A., Barcelona (an Air Products company) for their technical support
and Marta Pulido, MD, for editing the manuscript and editorial
assistance.
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Footnotes
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Abbreviation: NO = nitric oxide
Received for publication April 18, 2000.
Accepted for publication August 10, 2000.
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References
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Roberts, JD, Polaner, DM, Lang, P, et al (1992) Inhaled nitric oxide in persistent pulmonary hypertension of the newborn. Lancet 340,818-819[CrossRef][ISI][Medline]
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Snell, GI, Salamonsen, RF, Bergin, P, et al (1995) Inhaled nitric oxide used as a bridge to heart-lung transplantation in a patient with end-stage pulmonary hypertension. Am J Respir Crit Care Med 151,1263-1266[Abstract]
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Channick, R, Newhart, J, Johnson, W, et al (1996) Pluse delivery of inhaled nitric oxide to patients with primary pulmonary hypertension. Chest 109,1545-1549[Abstract/Free Full Text]
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Rossaint, R, Falke, KJ, López, F, et al (1993) Inhaled nitric oxide for the adult respiratory distress syndrome. N Engl J Med 328,399-405[Abstract/Free Full Text]
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Adatia, I, Lillehei, C, Arnold, JH, et al (1994) Inhaled nitric oxide in the treatment of postoperative graft dysfunction after lung transplantation. Ann Thorac Surg 57,1311-1318[Abstract]
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Robbins, IM, Christman, BW, Newman, JH, et al (1998) A survey of diagnostic practices and the use of epoprostenol in patients with primary pulmonary hypertension. Chest 114,1269-1275[Abstract/Free Full Text]
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Abstract
Introduction
