Inhaliertes Stickstoffmonoxid zur Behandlung refraktärer Hypoxämie bei ARDS–Patienten

Zusammenfassung

Das schwere akute Lungenversagen (acute respiratory distress syndrome, ARDS) ist durch eine Fehlverteilung des pulmonalen Blutflusses in nicht ventilierte, atelektatische Lungenareale charakterisiert, welche ihrerseits die Ursache für einen ausgeprägten intrapulmonalen Rechts–links–Shunt mit der Konsequenz einer arteriellen Hypoxämie bildet. Eine therapeutische Intervention zur selektiven Beeinflussung des pulmonalen Blutflusses, mit der sowohl der Gasaustausch verbessert als auch der pulmonalarterielle Druck gesenkt werden kann, steht mit der Anwendung von inhaliertem Stickstoffmonoxid (iNO) zur Verfügung. Obwohl randomisierte kontrollierte Studien bisher keinen signifikanten Effekt auf die Überlebensrate ergaben, stellt iNO dennoch derzeit eine klinisch relevante Option zur Notfallbehandlung von therapierefraktärer Hypoxämie dar und ist daher wichtiger Bestandteil eines Gesamtkonzeptes der ARDS–Behandlung in spezialisierten Zentren.

Abstract

The acute respiratory distress syndrome (ARDS) is characterized by a maldistribution of pulmonary blood flow towards non–ventilated atelectatic lung areas being the main reason for intrapulmonary right–to–left shunt with the consequence of severe arterial hypoxemia. The application of inhaled nitric oxide (iNO) is a therapeutic option to selectively influence pulmonary blood flow in order to improve arterial oxygenation and to decrease pulmonary artery pressure without relevant systemic side effects. Although randomized controlled trials demonstrated no survival benefit in patient populations covering the entire severity range of acute lung injury, iNO represents a feasible rescue treatment for ARDS patients with severe refractory hypoxemia and is, therefore, an important option for ARDS therapy in specialized centers.

Schlüsselwörter:

ARDS - refraktäre Hypoxämie - pulmonaler Gasaustausch - selektive pulmonale Vasodilatation - iNO

Keywords:

ARDS - refractory hypoxemia - pulmonary gas exchange - selective pulmonary vasodilation - iNO

Kernaussagen

• Die selektive pulmonale Vasodilatation mit iNO ermöglicht bei Patienten mit akutem Lungenversagen eine Umverteilung des Blutflusses von Shunt–Arealen zu ventilierten Lungenbereichen.

• Inhaliertes NO verbessert in der akuten Phase der Anwendung die arterielle Oxygenierung sowie die Hämodynamik und erlaubt die Reduktion von Beatmungsdrücken und FiO₂.

• Zur Verbesserung des Gasaustausches sollte iNO in Konzentrationen < 10 ppm appliziert werden.

• Bei ARDS–Patienten mit gegenüber konventionellen Therapieoptionen refraktärer Hypoxämie stellt iNO eine sinnvolle Notfallmaßnahme dar.

Literatur

• 1 Ware LB, Matthay MA.. The acute respiratory distress syndrome.  N Engl J Med. 2000;  342 1334-1349
• 2 Seeley EJ, McAuley DF, Eisner M, Miletin M, Matthay MA, Kallet RH.. Predictors of mortality in acute lung injury during the era of lung–protective ventilation. Thorax (im Druck) (Online bereits verfügbar als doi:10.1136/thx.2007.093658)
• 3 Laudi S, Busch T, Bercker S, Donaubauer B, Kaisers U.. (Therapeutic options for patients with acute lung injury).  Anasthesiol Intensivmed Notfallmed Schmerzther. 2007;  42 794-9
• 4 Meade MO, Cook DJ, Guyatt GH, Slutsky AS, Arabi YM, Cooper DJ, Davies AR, Hand LE, Zhou Q, Thabane L, Austin P, Lapinsky S, Baxter A, Russell J, Skrobik Y, Ronco JJ, Stewart TE. Lung Open Ventilation Study Investigators. . Ventilation strategy using low tidal volumes, recruitment maneuvers, and high positive end–expiratory pressure for acute lung injury and acute respiratory distress syndrome: a randomized controlled trial.  JAMA. 2008;  299 637-45
• 5 Palmer RM, Ferrige AG, Moncada S.. Nitric oxide release accounts for the biological activity of endothelium–derived relaxing factor.  Nature. 1987;  327 524-526
• 6 Ignarro LJ, Buga M, Wood KS, Byrns RE, Chaudhuri G.. Endothelium–derived relaxing factor produced and released from artery and vein is nitric oxide.  Proc Natl Acad Sci USA. 1987;  84 9265-9269
• 7 Frostell C, Fratacci MD, Wain JC, Jones R, Zapol WM.. Inhaled nitric oxide. A selective pulmonary vasodilator reversing hypoxic pulmonary vasoconstriction.  Circulation. 1991;  83 2038-2047
• 8 Pison U, Lopez FA, Heidelmeyer CF, Rossaint R, Falke KJ.. Inhaled nitric oxide reverses hypoxic pulmonary vasoconstriction without impairing gas exchange.  J Appl Physiol. 1993;  74 1287-1292
• 9 Frostell CG, Blomqvist H, Hedenstierna G, Lundberg J, Zapol WM.. Inhaled nitric oxide selectively reverses human hypoxic pulmonary vasoconstriction without causing systemic vasodilation.  Anesthesiology. 1993;  78 427-435
• 10 Higenbottam TW, Pepke–Zaba J, Scott J, Woolman P, Coutts C, Wallock J.. Inhaled Endothelium Derived–Relaxing Factor (EDRF) in primary hypertension (PPH).  Am Rev Respir Dis. 1988;  137
• 11 Rimar S, Gillis CN.. Selective pulmonary vasodilation by inhaled nitric oxide is due to hemoglobin inactivation.  Circulation. 1993;  88 2884-2887
• 12 Rossaint R, Falke K, Lopez F, Slama K, Pison U, Zapol W.. Inhaled nitric oxide for the adult respiratory distress syndrome.  N Engl J Med. 1993;  328 399-405
• 13 Puybasset L, Rouby JJ, Mourgeon E, Cluzel P, Souhil Z, Law–Koune JD, Stewart T, Devilliers C, Lu Q, Roche S, Kalfon B, Vicaut E, Viars P.. Factors influencing cardiopulmonary effects of inhaled nitric oxide in acute respiratory failure.  Am J Respir Crit Care Med. 1995;  152 318-328
• 14 Papazian L, Bregeon F, Gaillat F, Thirion X, Gainnier M, Gregoire R, Saux P, Gouin F, Jammes Y, Auffray JP.. Respective and combined effects of prone position and inhaled nitric oxide in patients with acute respiratory distress syndrome.  Am J Respir Crit Care Med. 1998;  157 580-585
• 15 Jolliet P, Bulpa P, Ritz M, Ricou B, Lopez J, Chevrolet JC.. Additive beneficial effects of the prone position, nitric oxide, and almitrine bismesylate on gas exchange and oxygen transport in acute respiratory distress syndrome.  Crit Care Med. 1997;  25 786-794
• 16 Germann P, Poschl G, Leitner C, Urak G, Ullrich R, Faryniak B, Roder G, Kaider A, Sladen R.. Additive effect of nitric oxide inhalation on the oxygenation benefit of the prone position in the adult respiratory distress syndrome.  Anesthesiology. 1998;  89 1401-1406
• 17 Martinez M, Diaz E, Joseph D, Villagra A, Mas A, Fernandez R, Blanch L.. Improvement in oxygenation by prone position and nitric oxide in patients with acute respiratory distress syndrome.  Intensive Care Med. 1999;  25 29-36
• 18 Borelli M, Lampati L, Vascotto E, Fumagalli R, Pesenti A.. Hemodynamic and gas exchange response to inhaled nitric oxide and prone positioning in acute respiratory distress syndrome patients.  Crit Care Med. 2000;  28 2707-2712
• 19 Dupont H, Mentec H, Cheval C, Moine P, Fierobe L, Timsit JF.. Short–term effect of inhaled nitric oxide and prone positioning on gas exchange in patients with severe acute respiratory distress syndrome.  Crit Care Med. 2000;  28 304-308
• 20 Gommers D, Hartog A, van Veen A, Lachmann B.. Improved oxygenation by nitric oxide is enhanced by prior lung reaeration with surfactant, rather than positive end–expiratory pressure, in lung–lavaged rabbits.  Crit Care Med. 1997;  25 1868-1873
• 21 Houmes RJM, Hartog A, Verbrugge SJC, Böhm S, Lachmann B.. Combining partial liquid ventilation with nitric oxide to improve gas exchange in acute lung injury.  Intensive Care Med. 1997;  23 163-169
• 22 Bigatello LM, Hurford WE, Kacmarek RM, Roberts JD, Zapol WM.. Prolonged inhalation of low concentrations of nitric oxide in patients with severe adult respiratory distress syndrome. Effects on pulmonary hemodynamics and oxygenation.  Anesthesiology. 1994;  80 761-770
• 23 Gerlach H, Rossaint R, Pappert D, Falke KJ.. 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. 1993;  23 499-502
• 24 Gerlach H, Falke KJ.. Low levels of inhaled nitric oxide in acute lung injury. In: Zapol WM, Bloch KD, eds. Lung biology in health and disease, Vol. 98: Nitric oxide and the lung. New York: Marcel Dekker 1997: 271-285
• 25 Manktelkow C, Bigatello LM, Hess D, Hurford WE.. Physiologic determinants of the response to inhaled nitric oxide in patients with acute respiratory distress syndrome.  Anesthesiology. 1997;  87 297-307
• 26 Young JD, Brampton WJ, Knighton JD, Finfer SR.. Inhaled nitric oxide in acute respiratory failure in adults.  Br J Anaesth. 1994;  73 499-502
• 27 Scherrer U, Vollenweider L, Delabays A, Savcic M, Eichenberger U, Kleger G–R, Fikrle A, Ballmer PE, Nicod P, Bärtsch P.. Inhaled nitric oxide for high–altitude pulmonary edema.  N Engl J Med. 1996;  334 624-629
• 28 Barberà JA, Roger N, Roca J, Rovira I, Higenbottam TW, Rodriguez–Roisin R.. Worsening of pulmonary gas exchange with nitric oxide inhalation in chronic obstructive pulmonary disease.  Lancet. 1996;  347 436-440
• 29 Holzmann A, Bloch KD, Sanchez LS, Filippov G, Zapol WM.. Hyporesponsiveness to inhaled nitric oxide in isolated perfused lungs from endotoxin–challenged rats.  Am J Physiol. 1996;  271 981-986
• 30 Holzmann A, Manktelow C, Taut FJH, Bloch KD, Zapol WM.. Inhibition of nitric oxide synthase prevents hyporesponsiveness to inhaled nitric oxide in lungs from endotoxin–challenged rats.  Anesthesiology. 1999;  91 215-221
• 31 Giaid A, Yanagisawa M, Langleben D, Michel RP, Levy R, Shennib H, Kimura S, Masaki T, Duguid WP, Stewart DJ.. Expression of endothelin–1 in the lungs of patients with pulmonary hypertension.  N Engl J Med. 1993;  328 1732-1739
• 32 Gandhi CR, Berkowitz DE, Watkins Endothelins. WD.. Biochemistry and pathophysiologic actions.  Anesthesiology. 1994;  80 892-905
• 33 Langleben D, DeMarchie M, Laporta D, Spanier AH, Schlesinger DJ. RD Stewart. Endothelin–1 in acute lung injury and the adult respiratory distress syndrome.  Am Rev Respir Dis. 1993;  148 1648-1650
• 34 Druml W, Steltzer H, Waldhäusl W, Lenz K, Hammerle A, Vierhapper H, Gasic S, Wagner OF.. Endothelin–1 in adult respiratory distress syndrome.  Am Rev Respir Dis. 1993;  148 1169-73
• 35 Mitaka C, Hirata Y, Nagura T, Tsunoda Y, Amaha K.. Circulating endothelin–1 concentrations in acute respiratory failure.  Chest. 1993;  104 476-480
• 36 Albertine KH, Wana ZM, Michael JR.. Expression of endothelial nitric oxide synthase, inducible nitric oxide synthase and endothelin–1 in lungs of subjects who died with ARDS.  Chest. 1999;  116
• 37 Busch T, Petersen B, Deja M, Donaubauer B, Laudi S, Jaumann S, Bercker S, Boemke W, Kaisers U.. Endothelin–1 influences the efficacy of inhaled nitric oxide in experimental acute lung injury.  Exp Biol Med (Maywood). 2006;  231 974-8
• 38 Gerlach H, Keh D, Semmerow A, Busch T, Lewandowski K, Pappert DM, Rossaint R, Falke KJ.. Dose–response characteristics during long–term inhalation of nitric oxide in patients with severe acute respiratory distress syndrome: a prospective, randomized, controlled study.  Am J Respir Crit Care Med. 2003;  167 1008-15
• 39 Mira JP, Monchi M, Brunet F, Fierobe L, Dhainaut JF, Dinh–Xuan AT.. Lack of efficacy of inhaled nitric oxide in ARDS.  Intensive Care Med. 1994;  20 532
• 40 Lundin S, Nathorst U Westfelt, Stenquist O, Blomqvist H, Lindh A, Berggren L, Arvidsson S, Rudberg U, Frostell CG.. Response to nitric oxide inhalation in early acute lung injury.  Intensive Care Med. 1996;  22 728-734
• 41 Rossaint R, Gerlach H, Schmidt–Ruhnke H, Pappert D, Lewandowski K, Steudel W, Falke K.. Efficacy of inhaled nitric oxide in patients with severe ARDS.  Chest. 1995;  107 1107-1115
• 42 Röttgen R, Busch T, Lohbrunner H, Einfeld H, Deja M, Schroeder RJ, Weber–Carstens S, Falke KJ, Felix R, Kaisers U.. (Computed tomographic criteria as expected effect to inhaled nitric oxide in patients with severe acute respiratory distress syndrome).  Rofo. 2005;  177 805-11
• 43 Michael JR, Barton RG, Saffle JR, Mone M, Markewitz BA, Hillier K, Elstad MR, Campbell EJ, Troyer BE, Whatley RE, Liou TG, Samuelson WM, Carveth HJ, Hinson DM, Morris SE, Davis BL, Day RW.. Inhaled nitric oxide versus conventional therapy: effect on oxygenation in ARDS.  Am J Respir Crit Care Med. 1998;  157 1372-1380
• 44 Troncy E, Collet JP, Shapiro S, Guimond JG, Blair L, Ducruet T, Francoeur M, Charbonneau M, Blaise G.. Inhaled nitric oxide in acute respiratory distress syndrome: a pilot randomized controlled study.  Am J Respir Crit Care Med. 1998;  157 1483-1488
• 45 Dellinger RP, Zimmerman JL, Taylor RW, Straube RC, Hauser DL, Criner GJ, Davis Jr K, Hyers TM, Papadakos P.. Effects of inhaled nitric oxide in patients with acute respiratory distress syndrome: results of a randomized phase II trial. Inhaled Nitric Oxide in ARDS Study Group.  Crit Care Med. 1998;  26 15-23
• 46 Bernard GR, Artigas A, Brigham KL, Carlet J, Falke K, Hudson L, Lamy M, Legall JR, Morris A, Spragg R.. The American–European consensus conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial coordination.  Am J Respir Crit Care Med. 1994;  149 818-824
• 47 Lundin S, Mang H, Smithies M, Stenqvist O, Frostell C.. Inhalation of nitric oxide in acute lung injury: results of a European multicentre study.  Intensive Care Med. 1999;  25 911-919
• 48 Taylor RW, Zimmerman JL, Dellinger RP, Straube RC, Criner GJ, Davis K, Kelly KM, Smith TC, Small RJ. Inhaled Nitric Oxide in ARDS Study Group. . Low–dose inhaled nitric oxide in patients with acute lung injury: a randomized controlled trial.  JAMA. 2004;  291 1603-9
• 49 Kaisers U, Deja M, Boemke W, Busch T.. Inhaled nitric oxide in acute lung injury.  JAMA. 2004;  292 327
• 50 Sokol S, Jacobs JE, Bohn D.. Inhaled nitric oxide for acute hypoxemic respiratory failure in children and adults (Cochrane Review). In: The Cochrane Library, Issue 3, 2001. Oxford: Update Software
• 51 Adhikari NK, Burns KE, Friedrich JO, Granton JT, Cook DJ, Meade MO.. Effect of nitric oxide on oxygenation and mortality in acute lung injury: systematic review and meta–analysis.  BMJ. 2007;  14 779-86
• 52 Germann P, Braschi A, Della G Rocca, Dinh–Xuan AT, Falke K, Frostell C, Gustafsson LE, Hervé P, Jolliet P, Kaisers U, Litvan H, Macrae DJ, Maggiorini M, Marczin N, Mueller B, Payen D, Ranucci M, Schranz D, Zimmermann R, Ullrich R.. Inhaled nitric oxide therapy in adults: European expert recommendations.  Intensive Care Med. 2005;  31 1029-41
• 53 Walmrath D, Schneider T, Schermuly R, Olschewski H, Grimminger F, Seeger W.. Direct comparison of inhaled nitric oxide and aerosolized prostacyclin in acute respiratory distress syndrome.  Am J Respir Crit Care Med. 1996;  153 991-6
• 54 Kaisers U, Busch T, Wolf S, Lohbrunner, Wilkens K, Hocher B, Boemke W.. Inhaled endothelin A antagonist improves arterial oxygenation in experimental acute lung injury.  Intensive Care Med. 2000;  26 1334-1342