Skip to main content
Thorax logoLink to Thorax
. 2003 Apr;58(4):289–293. doi: 10.1136/thorax.58.4.289

Controlled prospective randomised trial on the effects on pulmonary haemodynamics of the ambulatory long term use of nitric oxide and oxygen in patients with severe COPD

K Vonbank 1, R Ziesche 1, T Higenbottam 1, L Stiebellehner 1, V Petkov 1, P Schenk 1, P Germann 1, L Block 1
PMCID: PMC1746623  PMID: 12668787

Abstract

Background: Pulmonary hypertension is a frequent complication of severe chronic obstructive pulmonary disease (COPD) and a major cause of morbidity and mortality in this condition. Based on the improved survival of these patients due to long term oxygen therapy and the potent and selective pulmonary vasodilation by inhaled nitric oxide, the safety and effectiveness of the combined inhalation of these two gases over a 3 month period was assessed.

Methods: Forty patients with secondary pulmonary hypertension due to COPD were randomly assigned to receive either oxygen alone or "pulsed" inhalation of nitric oxide with oxygen over a period of 3 months. "Pulsed" inhalation of nitric oxide was used to reduce pulmonary ventilation-perfusion mismatch and formation of toxic reaction products of nitric oxide and oxygen.

Results: Compared with oxygen alone, the combined inhalation of nitric oxide and oxygen caused a significant decrease in mean (SE) pulmonary artery pressure (from 27.6 (4.4) mm Hg to 20.6 (4.9) mm Hg, p<0.001) and pulmonary vascular resistance index (from 569.7 (208.1) to 351.3 (159.9) dyne•s-1•cm-5•m-2, p<0.001) without decreasing arterial oxygenation. Cardiac output increased by 0.5 litres (from 5.6 (1.3) l/min to 6.1 (1.0) l/min, p=0.025). Systemic haemodynamics and left heart function remained unchanged during this period and no increase in toxic reaction products of nitric oxide was observed.

Conclusions: This is the first controlled trial indicating that the "pulsed" inhalation of nitric oxide together with oxygen may be safely and effectively used for the long term treatment of severe COPD.

Full Text

The Full Text of this article is available as a PDF (145.9 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Ashutosh K., Phadke K., Jackson J. F., Steele D. Use of nitric oxide inhalation in chronic obstructive pulmonary disease. Thorax. 2000 Feb;55(2):109–113. doi: 10.1136/thorax.55.2.109. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Barberà J. A., Roger N., Roca J., Rovira I., Higenbottam T. W., Rodriguez-Roisin R. Worsening of pulmonary gas exchange with nitric oxide inhalation in chronic obstructive pulmonary disease. Lancet. 1996 Feb 17;347(8999):436–440. doi: 10.1016/s0140-6736(96)90011-2. [DOI] [PubMed] [Google Scholar]
  3. Cremona G., Higenbottam T. W., Bower E. A., Wood A. M., Stewart S. Hemodynamic effects of basal and stimulated release of endogenous nitric oxide in isolated human lungs. Circulation. 1999 Sep 21;100(12):1316–1321. doi: 10.1161/01.cir.100.12.1316. [DOI] [PubMed] [Google Scholar]
  4. Dinh-Xuan A. T., Higenbottam T. W., Clelland C. A., Pepke-Zaba J., Cremona G., Butt A. Y., Large S. R., Wells F. C., Wallwork J. Impairment of endothelium-dependent pulmonary-artery relaxation in chronic obstructive lung disease. N Engl J Med. 1991 May 30;324(22):1539–1547. doi: 10.1056/NEJM199105303242203. [DOI] [PubMed] [Google Scholar]
  5. Feigal David W., Gardner Susan N., McClellan Mark. Ensuring safe and effective medical devices. N Engl J Med. 2003 Jan 16;348(3):191–192. doi: 10.1056/NEJMp020170. [DOI] [PubMed] [Google Scholar]
  6. Ford P. C., Wink D. A., Stanbury D. M. Autoxidation kinetics of aqueous nitric oxide. FEBS Lett. 1993 Jul 12;326(1-3):1–3. doi: 10.1016/0014-5793(93)81748-o. [DOI] [PubMed] [Google Scholar]
  7. Franco-Cereceda A., Holm P., Brodin L. A., Liska J., Larsen F. F. ET-1 infusion increases systemic vascular resistance and depresses cardiac output in patients with chronic hypoxaemia and pulmonary hypertension. Scand Cardiovasc J. 1999;33(3):151–156. doi: 10.1080/14017439950141777. [DOI] [PubMed] [Google Scholar]
  8. Fujii T., Otsuka T., Tanaka S., Kanazawa H., Hirata K., Kohno M., Kurihara N., Yoshikawa J. Plasma endothelin-1 level in chronic obstructive pulmonary disease: relationship with natriuretic peptide. Respiration. 1999;66(3):212–219. doi: 10.1159/000029380. [DOI] [PubMed] [Google Scholar]
  9. Germann P., Ziesche R., Leitner C., Roeder G., Urak G., Zimpfer M., Sladen R. Addition of nitric oxide to oxygen improves cardiopulmonary function in patients with severe COPD. Chest. 1998 Jul;114(1):29–35. doi: 10.1378/chest.114.1.29. [DOI] [PubMed] [Google Scholar]
  10. Katayama Y., Higenbottam T. W., Cremona G., Akamine S., Demoncheaux E. A., Smith A. P., Siddons T. E. Minimizing the inhaled dose of NO with breath-by-breath delivery of spikes of concentrated gas. Circulation. 1998 Dec 1;98(22):2429–2432. doi: 10.1161/01.cir.98.22.2429. [DOI] [PubMed] [Google Scholar]
  11. Katayama Y., Higenbottam T. W., Diaz de Atauri M. J., Cremona G., Akamine S., Barbera J. A., Rodrìguez-Roisin R. Inhaled nitric oxide and arterial oxygen tension in patients with chronic obstructive pulmonary disease and severe pulmonary hypertension. Thorax. 1997 Feb;52(2):120–124. doi: 10.1136/thx.52.2.120. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Kirschke David L., Jones Timothy F., Craig Allen S., Chu Patricia S., Mayernick Glenda G., Patel Jayesh A., Schaffner William. Pseudomonas aeruginosa and Serratia marcescens contamination associated with a manufacturing defect in bronchoscopes. N Engl J Med. 2003 Jan 16;348(3):214–220. doi: 10.1056/NEJMoa021791. [DOI] [PubMed] [Google Scholar]
  13. Kouyoumdjian C., Adnot S., Levame M., Eddahibi S., Bousbaa H., Raffestin B. Continuous inhalation of nitric oxide protects against development of pulmonary hypertension in chronically hypoxic rats. J Clin Invest. 1994 Aug;94(2):578–584. doi: 10.1172/JCI117372. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Lewis R. S., Deen W. M. Kinetics of the reaction of nitric oxide with oxygen in aqueous solutions. Chem Res Toxicol. 1994 Jul-Aug;7(4):568–574. doi: 10.1021/tx00040a013. [DOI] [PubMed] [Google Scholar]
  15. Lopez A. D., Murray C. C. The global burden of disease, 1990-2020. Nat Med. 1998 Nov;4(11):1241–1243. doi: 10.1038/3218. [DOI] [PubMed] [Google Scholar]
  16. Lupi-Herrera E., Seoane M., Verdejo J. Hemodynamic effect of hydralazine in advanced, stable chronic obstructive pulmonary disease with cor pulmonale. Immediate and short-term evaluation at rest and during exercise. Chest. 1984 Feb;85(2):156–163. doi: 10.1378/chest.85.2.156. [DOI] [PubMed] [Google Scholar]
  17. Melot C., Hallemans R., Naeije R., Mols P., Lejeune P. Deleterious effect of nifedipine on pulmonary gas exchange in chronic obstructive pulmonary disease. Am Rev Respir Dis. 1984 Oct;130(4):612–616. doi: 10.1164/arrd.1984.130.4.612. [DOI] [PubMed] [Google Scholar]
  18. Nakanishi K., Tajima F., Nakata Y., Osada H., Tachibana S., Kawai T., Torikata C., Suga T., Takishima K., Aurues T. Expression of endothelin-1 in rats developing hypobaric hypoxia-induced pulmonary hypertension. Lab Invest. 1999 Nov;79(11):1347–1357. [PubMed] [Google Scholar]
  19. Nenci G. G., Berrettini M., Todisco T., Costantini V., Parise P. Effects of dipyridamole on the hypoxemic pulmonary hypertension of patients with chronic obstructive pulmonary disease. Respiration. 1988;53(1):13–19. doi: 10.1159/000195390. [DOI] [PubMed] [Google Scholar]
  20. Pepke-Zaba J., Higenbottam T. W., Dinh-Xuan A. T., Stone D., Wallwork J. Inhaled nitric oxide as a cause of selective pulmonary vasodilatation in pulmonary hypertension. Lancet. 1991 Nov 9;338(8776):1173–1174. doi: 10.1016/0140-6736(91)92033-x. [DOI] [PubMed] [Google Scholar]
  21. Roberts J. D., Jr, Fineman J. R., Morin F. C., 3rd, Shaul P. W., Rimar S., Schreiber M. D., Polin R. A., Zwass M. S., Zayek M. M., Gross I. Inhaled nitric oxide and persistent pulmonary hypertension of the newborn. The Inhaled Nitric Oxide Study Group. N Engl J Med. 1997 Feb 27;336(9):605–610. doi: 10.1056/NEJM199702273360902. [DOI] [PubMed] [Google Scholar]
  22. Roger N., Barberà J. A., Roca J., Rovira I., Gómez F. P., Rodriguez-Roisin R. Nitric oxide inhalation during exercise in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 1997 Sep;156(3 Pt 1):800–806. doi: 10.1164/ajrccm.156.3.9611051. [DOI] [PubMed] [Google Scholar]
  23. Sajkov D., Wang T., Frith P. A., Bune A. J., Alpers J. A., McEvoy R. D. A comparison of two long-acting vasoselective calcium antagonists in pulmonary hypertension secondary to COPD. Chest. 1997 Jun;111(6):1622–1630. doi: 10.1378/chest.111.6.1622. [DOI] [PubMed] [Google Scholar]
  24. Siafakas N. M., Vermeire P., Pride N. B., Paoletti P., Gibson J., Howard P., Yernault J. C., Decramer M., Higenbottam T., Postma D. S. Optimal assessment and management of chronic obstructive pulmonary disease (COPD). The European Respiratory Society Task Force. Eur Respir J. 1995 Aug;8(8):1398–1420. doi: 10.1183/09031936.95.08081398. [DOI] [PubMed] [Google Scholar]
  25. Sitbon O., Brenot F., Denjean A., Bergeron A., Parent F., Azarian R., Herve P., Raffestin B., Simonneau G. Inhaled nitric oxide as a screening vasodilator agent in primary pulmonary hypertension. A dose-response study and comparison with prostacyclin. Am J Respir Crit Care Med. 1995 Feb;151(2 Pt 1):384–389. doi: 10.1164/ajrccm.151.2.7842196. [DOI] [PubMed] [Google Scholar]
  26. Weitzenblum E., Hirth C., Ducolone A., Mirhom R., Rasaholinjanahary J., Ehrhart M. Prognostic value of pulmonary artery pressure in chronic obstructive pulmonary disease. Thorax. 1981 Oct;36(10):752–758. doi: 10.1136/thx.36.10.752. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Weitzenblum E., Kessler R., Oswald M., Fraisse P. Medical treatment of pulmonary hypertension in chronic lung disease. Eur Respir J. 1994 Jan;7(1):148–152. doi: 10.1183/09031936.94.07010148. [DOI] [PubMed] [Google Scholar]
  28. Weitzenblum E., Sautegeau A., Ehrhart M., Mammosser M., Pelletier A. Long-term oxygen therapy can reverse the progression of pulmonary hypertension in patients with chronic obstructive pulmonary disease. Am Rev Respir Dis. 1985 Apr;131(4):493–498. doi: 10.1164/arrd.1985.131.4.493. [DOI] [PubMed] [Google Scholar]
  29. Yoshida M., Taguchi O., Gabazza E. C., Kobayashi T., Yamakami T., Kobayashi H., Maruyama K., Shima T. Combined inhalation of nitric oxide and oxygen in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 1997 Feb;155(2):526–529. doi: 10.1164/ajrccm.155.2.9032189. [DOI] [PubMed] [Google Scholar]

Articles from Thorax are provided here courtesy of BMJ Publishing Group

RESOURCES