Nitric Oxide Inhalation in ARDS

  • H. Gerlach
  • R. Rossaint
  • K. J. Falke
Part of the Update in Intensive Care and Emergency Medicine book series (UICM, volume 24)


The acute adult respiratory distress syndrome (ARDS), a disorder described by Ashbaugh et al. [1] with a mortality of approximately 60–70%, is characterized by a heterogeneous deterioration of both alveolar ventilation and pulmonary perfusion due to edema and local inflammation, associated with gas space collapse, vasoconstriction and vascular obliteration [2, 3]. The mechanisms of the acute, diffuse pulmonary inflammation cause non-cardiogenic pulmonary edema, pulmonary hypertension, a decrease in lung compliance, and progressive hypoxemia due to an increasing intrapulmonary shunt. Pulmonary hypertension and an aggressive mechanical ventilatory strategy using high inspiratory oxygen concentrations (FiO2) and high peak inspiratory pressures (PIP) are possible pathogenic mechanisms which contribute to continuing pure results [4]. Pulmonary hypertension induces a rise in the microvascular filtration pressure [5], enhancing the development of interstitial pulmonary edema [6] and right ventricular dysfunction [7, 8]. Reduction of pulmonary vascular resistance (PVR) by systemically infused vasodilating drugs was shown to exert a beneficial effect in ARDS by lowering pulmonary artery pressure (PAP), although the intrapulmonary right-to-left shunt increases by this treatment; because of the global effect on the vasculature, the use of systemic vasodilators is limited [9]. The concomitant dilation of the systemic circulation causes arterial hypertension possibly affecting the blood flow to various organs. In addition, vasodilation in the pulmonary vasculature gives rise to increase blood flow to areas of intrapulmonary shunt, thereby compromising oxygenation even further [9,10]. This dilation may require further increase in the FiO2 and airway pressures needed for the maintenance of normal arterial blood gases. High FiO2 and high PIP have to be regarded as factors which contribute to the progression of the disease [11,12].


Nitric Oxide Pulmonary Hypertension Pulmonary Artery Pressure Adult Respiratory Distress Syndrome Right Ventricular Ejection Fraction 
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  1. 1.
    Ashbaugh DG, Bigelow DB, Petty TL, Levine BE (1967) Acute respiratory distress in adults. Lancet 2:319–323PubMedCrossRefGoogle Scholar
  2. 2.
    Zapol WM, Snider MT (1977) Pulmonary hypertension in severe acute respiratory failure. N Engl J Med 296:476–480PubMedCrossRefGoogle Scholar
  3. 3.
    Rinaldo JE, Rogers RM (1982) Adult respiratory distress syndrome. Changing concepts of lung injury and repair. N Engl J Med 306:900–909PubMedCrossRefGoogle Scholar
  4. 4.
    European ARDS Collaborative Working Group (1988) Adult respiratory distress syndrome (ARDS): Clinical predictors, prognostic factors and outcome. Intensive Care Med 14 (Suppl. 1): A300 (Abst)Google Scholar
  5. 5.
    Erdmann AJ, Vaughan TR Jr, Brigham KL, et al (1975) Effect of increased vascular pressure on lung fluid balance in unanesthetized sheep. Circ Res 37:271–284PubMedGoogle Scholar
  6. 6.
    Gottlieb SS, Wood LDH, Hansen DE, Long GR (1987) The effect of nitroprusside on pulmonary edema, oxygen exchange, and blood flow in hydrochloric acid aspiration. Anesthesiology 67:203–210PubMedCrossRefGoogle Scholar
  7. 7.
    Sibbald WJ, Driedger AA, Myers ML, Short Al, Wells GA (1983) Biventricular function in the adult respiratory distress syndrome. Chest 84:126–134PubMedCrossRefGoogle Scholar
  8. 8.
    Vlahakes GJ, Turley K, Hoffmann JI (1981) The pathophysiology of failure in acute right ventricular hypertension: Hemodynamic and biochemical correlations. Circulation 63:87–95PubMedCrossRefGoogle Scholar
  9. 9.
    Radermacher P, Santak B, Becker H, Falke KJ (1989) Prostaglandin Ei and nitroglycerin reduce pulmonary capillary pressure but worsen ventilation-perfusion distributions in patients with adult respiratory distress syndrome. Anesthesiology 70: 601–606PubMedCrossRefGoogle Scholar
  10. 10.
    Zapol WM, Snider MT, Rie MA, Frikker M, Quimm DA (1985) Pulmonary circulation during adult respiratory distress syndrome. In: Zapol WM, Falke KJ (eds) Acute Respiratory Failure. Marcel Dekker, New York, pp 241–273Google Scholar
  11. 11.
    Haschek WM, Reiser KM, Klein-Szanto AJ, et al (1983) Potentiation of butylated hydroxytoluene-induced acute lung damage by oxygen. Cell kinetics and collagen metabolism. Am Rev Respir Dis 127:28–34PubMedGoogle Scholar
  12. 12.
    Kolobow T, Moretti MP, Fumagalli R, et al (1987) Severe impairment in lung function induced by high peak airway pressure during mechanical ventilation. An experimental study. Am Rev Respir Dis 135:312–315PubMedGoogle Scholar
  13. 13.
    Zapol WM, Snider MT, Hill JD, et al (1979) Extracorporeal membrane oxygenation in severe acute respiratory failure. A randomized prospective study. JAMA 242: 2193–2196PubMedCrossRefGoogle Scholar
  14. 14.
    Rossaint R, Slama K, Lewandowski K, et al (1992) Extracorporeal lung assist with heparin-coated systems. Int J Artif Organs 15:29–34PubMedGoogle Scholar
  15. 15.
    Tharratt RS, Allen RP, Albertson TE (1988) Pressure-controlled inverse ratio ventilation in severe adult respiratory failure. Chest 94:755–762PubMedCrossRefGoogle Scholar
  16. 16.
    Suchyta MR, Clemmer TP, Orme JFJ, Morris AH, Elliott CG (1991) Increased survival of ARDS patients with severe hypoxemia (ECMO) criteria. Chest 99:951–955PubMedCrossRefGoogle Scholar
  17. 17.
    Gerlach H, Esposito C, Stern DM (1990) Modulation of endothelial hemostatic properties An active role in the host response. Annu Rev Med 41:15–24PubMedCrossRefGoogle Scholar
  18. 18.
    Lie M, Sejersted OM, Kiil F (1970) Local regulation of vascular cross section during changes in femoral arterial blood flow in dogs. Circ Res 27:727–737PubMedGoogle Scholar
  19. 19.
    Furchgott RF, Zawadzki JV (1980) The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 288:373–376PubMedCrossRefGoogle Scholar
  20. 20.
    Ignarro LJ, Buga GM, Wood KS, Byrns RE, Chaudhuri G (1987) Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide. Proc Natl Acad Sci USA 84:9265–9269PubMedCrossRefGoogle Scholar
  21. 21.
    Palmer RM, Ferrige AG, Moncada S (1987) Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature 327:524–526PubMedCrossRefGoogle Scholar
  22. 22.
    Palmer RM, Rees DD, Ashton DS, Moncada S (1988) L-arginine is the physiological precursor for the formation of nitric oxide in endothelium-dependent relaxation. Biochem Biophys Res Commun 153:1251–1256PubMedCrossRefGoogle Scholar
  23. 23.
    Brenner BM, Troy JL, Ballermann BJ (1989) Endothelium-dependentvascular responses. J Clin Invest 84:1373–1378PubMedCrossRefGoogle Scholar
  24. 24.
    Ignarro LJ, Lippton H, Edwards JC, et al (1981) Mechanism of vascular smooth muscle relaxation by organic nitrates, nitrites, nitroprusside and nitric oxide: Evidence for the involvement of S-nitrosothiols as active intermediates. J Pharmacol Exp Ther 218: 739–749PubMedGoogle Scholar
  25. 25.
    Gibson QH, Roughton FJW (1957) The kinetics of equilibria of the reactions of nitric oxide with sheep hemoglobin. J Physiol 136:507–526PubMedGoogle Scholar
  26. 26.
    Oda H, Nogami H, Kusumoto S, Nakajima T, Kurata A, Imai K (1976) Long-term exposure to nitric oxide in mice. J Jpn Soc Air Pollut 11:150–160Google Scholar
  27. 27.
    Hugod C (1979) Effect of exposure to 43 ppm nitric oxide and 3.6 ppm nitrogen dioxide on rabbit lung. A light and electron microscopic study. Int Arch Occup Environ Health 42:159–167PubMedCrossRefGoogle Scholar
  28. 28.
    Higenbottam T, Pepke-Zaba J, Scott J, Woolman P, Coutts C, Wallwork J (1988) Inhaled “endothelium-derived relaxing factor” (EDRF) in primary hypertension. Am Rev Respir Dis 137:107A (Abst)Google Scholar
  29. 29.
    Pepke-Zaba J, Higenbottam TW, Dinh-Xuan AT, Stone D, Wallwork J (1991) Inhaled nitric oxide as a cause of selective pulmonary vasodilatation in pulmonary hypertension. Lancet 338:1173–1174PubMedCrossRefGoogle Scholar
  30. 30.
    Frostell C, Fratacci MD, Wain JC, Jones R, Zapol WM (1991) Inhaled nitric oxide. A selective pulmonary vasodilator reversing hypoxic pulmonary vasoconstriction. Circulation 83:2038–2047PubMedGoogle Scholar
  31. 31.
    Pison U, Lopez FA, Heidelmeyer CF, Rossaint R, Falke K (1993) Inhaled nitric oxide selectively reverses hypoxic pulmonary vasoconstriction without impairing pulmonary gas exchange. J Appl Physiol 74:7287–7292Google Scholar
  32. 32.
    Rossaint R, Falke KJ, Lopez F, Slama K, Pison U, Zapol WM (1993) Inhaled nitric oxide in adult respiratory distress syndrome. N Engl J Med 328:399–405PubMedCrossRefGoogle Scholar
  33. 33.
    Wagner PD, Saltzman HA, West JB (1974) Measurement of continuous distributions of ventilation-perfusion ratios: Theory. J Appl Physiol 36:588–599PubMedGoogle Scholar
  34. 34.
    Dupuy PM, Shore SA, Drazen JM, Frostell C, Hill WA, Zapol WM (1992) Bronchodilator action of inhaled nitric oxide in guinea pigs. J Clin Invest 90:421–428PubMedCrossRefGoogle Scholar
  35. 35.
    Roberts JD, Polander DM, Lang P, Zapol WM (1992) Inhaled nitric oxide in persistent pulmonary hypertension of the newborn. Lancet 340:818–819PubMedCrossRefGoogle Scholar
  36. 36.
    Kinsella JP, Neish SR, Shaffer E, Abman SH (1992) Low-dose inhalational nitric oxide in persistent pulmonary hypertension of the newborn. Lancet 340:819–820PubMedCrossRefGoogle Scholar
  37. 37.
    Levin DL, Heymann MA, Kitterman JA, et al (1976) Persistent pulmonary hypertension of the newborn infant. J Pediatr 89:626–630PubMedCrossRefGoogle Scholar
  38. 38.
    Dhainaut JF, Brunet F (1990) Right ventricular performance in adult respiratory distress syndrome. Eur Respir J 3(Suppl 11): 490–495Google Scholar
  39. 39.
    Radermacher P, Santak B, Wust HJ, Tarnow J, Falke KJ (1990) Prostacyclin and right ventricular function in patients with pulmonary hypertension associated with ARDS. Intensive Care Med 16:227–232PubMedCrossRefGoogle Scholar
  40. 40.
    Sibbald WJ, Driedger AA (1983) Right ventricular function in acute disease states: Pathophysiologic considerations. Crit Care Med 11:339–345PubMedCrossRefGoogle Scholar
  41. 41.
    Brunet F, Dhainaut JF, Devaux JY, Huyghebaert MF, Villenant D, Monsallier JF (1988) Right ventricular performance in patients with acute respiratory failure. Intensive Care Med 14:474–477PubMedCrossRefGoogle Scholar
  42. 42.
    Eddy AC, Rice CL (1989) The right ventricle: An emerging concern in the multiply injured patient. J Crit Care 4:58–66CrossRefGoogle Scholar
  43. 43.
    Sibbald WJ, Driedger AA, Cunningham DG, Cheung H (1986) Right and left ventricular performance in acute hypoxemic respiratory failure. Crit Care Med 14: 858–857CrossRefGoogle Scholar
  44. 44.
    Dhainaut JF, Lanore J J, De Gournay JM, et al (1988) Right ventricular dysfunction in patients with septic shock. Intensive Care Med 14:488–491PubMedCrossRefGoogle Scholar
  45. 45.
    Vincent JL, Reuse C, Frank N, Contempre B, Kahn RJ (1989) Right ventricular dysfunction in septic shock: Assessment by measurements of right ventricular ejection fraction using the thermodilution technique. Acta Anaesthesiol Scand 33:34–38PubMedCrossRefGoogle Scholar
  46. 46.
    Vincent JL, Reuse C, Kahn RJ (1988) Effect on right ventricular function of a change from dopamine to dobutamine in critically ill patients. Crit Care Med 16:659–662PubMedCrossRefGoogle Scholar
  47. 47.
    Wysocki M, Vignon P, Roupie E, et al (1993) Improvement in right ventricular function with inhaled nitric oxide in patients with the adult respiratory distress syndrome (ARDS) and permissive hypercapnia. Am Rev Respir Dis 147: A350 (Abst)Google Scholar
  48. 48.
    Gerlach H, Rossaint R, Pappert D, Falke KJ (1993) Time-course and dose-response of nitric oxide inhalation for systemic oxygenation and pulmonary hypertension in patients with adult respiratory distress syndrome. Eur J Clin Invest 23:499–502PubMedCrossRefGoogle Scholar
  49. 49.
    Roberts JD, Chen TY, Kawai N, et al (1993) Inhaled nitric oxide reverses pulmonary vasoconstriction in the hypoxic and acidotic newborn. Circ Res 72:246–254PubMedGoogle Scholar
  50. 50.
    Gerlach H, Pappert D, Lewandowski K, Rossaint R, Falke KJ (1993) Long-term inhalation with evaluated low doses of nitric oxide for selective improvement of oxygenation in patients with adult respiratory distress syndrome. Intensive Care Med 19: 443–449PubMedCrossRefGoogle Scholar
  51. 51.
    Villar J, Blazquez MA, Lubilio S, Quintana J, Manzano JL (1989) Pulmonary hypertension in acute respiratory failure. Crit Care Med 17:523–526PubMedCrossRefGoogle Scholar
  52. 52.
    Dinh-Xuan AT, Higenbottam TW, Clelland CA, et al (1991) Impairment of endothelium-dependent pulmonary-artery relaxation in chronic obstructive lung disease. N Engl J Med 324:1539–1547PubMedCrossRefGoogle Scholar
  53. 53.
    Stamler JS, Singel DJ, Loscalzo J (1992) Biochemistry of nitric oxide and its redox-activated forms. Science 258:1898–1902PubMedCrossRefGoogle Scholar
  54. 54.
    Radi R, Beckman JS, Bush KM, Freeman BA (1991) Peroxynitrite oxidation of sulfhydryls. J Biol Chem 266:4244–4250PubMedGoogle Scholar
  55. 55.
    Keilin D, Hartree EF (1937) Reaction of nitric oxide with haemoglobin and methaemoglobin. Nature 139:548–551CrossRefGoogle Scholar
  56. 56.
    Clutton-Brock J (1967) Two cases of poisoning by contamination of nitrous oxide with higher oxides of nitrogen during anaesthesia. Br J Anaesth 39:388–392PubMedCrossRefGoogle Scholar
  57. 57.
    Greenbaum R, Bay J, Hargreaves MD, et al (1967) Effects of higher oxides of nitrogen on the anaesthetized dog. Br J Anaesth 39:393–404PubMedCrossRefGoogle Scholar
  58. 58.
    Austin AT (1967) The chemistry of the higher oxides of nitrogen as related to the manufacture, storage and administration of nitrous oxide. Br J Anaesth 39:345–350PubMedCrossRefGoogle Scholar
  59. 59.
    Fontijn A, Sabadell AJ, Ronco RJ (1970) Homogenous chemiluminescent measurement of nitric oxide with ozone. Anal Chem 42:575–579CrossRefGoogle Scholar
  60. 60.
    Thomas HV, Mueller PK, Lyman RL (1968) Lipid peroxidation of lung lipids in rats exposed to nitrogen dioxide. Science 159:532–534PubMedCrossRefGoogle Scholar
  61. 61.
    Rasmussen TR, Kjaergaard SK, Tarp U, Pedersen OF (1992) Delayed effects of N02 exposure on alveolar permeability and glutathione peroxidase in healthy humans. Am Rev Respir Dis 146:654–659PubMedGoogle Scholar
  62. 62.
    Norman V, Keith CH (1965) Nitrogen oxides in tobacco smoke. Nature 205:915–916CrossRefGoogle Scholar
  63. 63.
    Higenbottam T, Borland C (1987) NO yields of contemporary UK, US and French cigarettes. Int J Epidemiol 16:31–34PubMedCrossRefGoogle Scholar
  64. 64.
    Centers for Disease Control (1988) Recommendations for occupational safety and health standard. MMWN 37 (Suppl): 5–7Google Scholar
  65. 65.
    Vallance P, Moncada S (1993) The role of endogenous nitric oxide in septic shock. New Horizons 1:77–86PubMedGoogle Scholar
  66. 66.
    Skwarski KM, Gorecka D, Sliwinski P, Hogg J, MacNee W (1993) The effects of cigarette smoking on pulmonary hemodynamics. Chest 103:1166–1172PubMedCrossRefGoogle Scholar
  67. 67.
    Gustafsson LE, Leone AM, Persson MG (1991) Endogenous nitric oxide is present in the exhaled air of rabbits, guinea pigs and humans. Biochem Biophys Res Commun 181:852–857PubMedCrossRefGoogle Scholar
  68. 68.
    Gerlach H, Rossaint R, Pappert D, Knorr M, Falke KF (1994) Autoinhalation of nitric oxide after endogenous synthesis in nasopharynx. Lancet 343:518–519PubMedCrossRefGoogle Scholar
  69. 69.
    Cremona G, Dinh-Xuan AT, Higenbottam TW (1991) Endothelium-derived relaxing factor and the pulmonary circulation. Lung 169:185–202PubMedCrossRefGoogle Scholar
  70. 70.
    Benzing A, Geiger K (1994) Inhaled nitric oxide lowers pulmonary capillary pressure and changes longitudinal distribution of pulmonary vascular resistance in patients with acute lung injury. Acta Anaesthesiol Scand 38:640–645PubMedCrossRefGoogle Scholar
  71. 71.
    Rogers NE, Ignarro LJ (1992) Constitutive nitric oxide synthase from cerebellum is reversibly inhibited by nitric oxide formed from L-arginine. Biochem Biophys Res Commun 189:242–249PubMedCrossRefGoogle Scholar
  72. 72.
    Assreuy J, Cunha FQ, Liew FY, Moncada S (1993) Feedback inhibition of nitric oxide synthase activity by nitric oxide. Br J Pharmacol 108:833–837PubMedGoogle Scholar
  73. 73.
    Hogman M, Frostell C, Arnberg H, Sandhagen B, Hedenstierna G (1994) Prolonged bleeding time during nitric oxide inhalation in the rabbit. Acta Physiol Scand 151: 125–129PubMedCrossRefGoogle Scholar
  74. 74.
    Hogman M, Frostell C, Arnberg H, Hedenstierna G (1993) Bleeding time prolongation and NO inhalation. Lancet 341:1664–1665PubMedCrossRefGoogle Scholar
  75. 75.
    Petros AJ, Cox PB, Bohn D (1992) Simple method for monitoring inhaled nitric oxide. Lancet 340:1167PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1995

Authors and Affiliations

  • H. Gerlach
  • R. Rossaint
  • K. J. Falke

There are no affiliations available

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