Supportive und adjunktive Therapiemaßnahmen bei akutem Lungenversagen

Zusammenfassung

Trotz einzelner positiver Ergebnisse hinsichtlich der Oxygenierung und physiologischer Variablen in meist kleineren, observationellen Untersuchungen, konnte bislang für keine der untersuchten adjunktiven und supportiven Therapiestrategien (z.B. pulmonale Vasodilatatoren, Glukokortikoide, Surfactant, Lagerungstherapie u.a.) eine Effektivität hinsichtlich der Verbesserung der Überlebensrate des akuten Lungenversagens in entsprechend dimensionierten und strukturierten Untersuchungen dargestellt werden.

Summary

Various supportive and adjunctive therapies to conventional mechanical ventilation have been evaluated in patients with acute lung injury and acute respiratory distress syndrome (e.g. nitric oxide, prone position, surfactant, glucocorticoids). Although some investigations have shown promising improvements in oxygenation and physiological variables, large randomized trials of adjunctive and supportive therapies showed no impact on survival.

Schlüsselwörter:

akutes Lungenversagen - adjunktive Therapie - supportive Therapie - Lungenödem - Management

Key words:

acute respiratory distress syndrome - nonventilatory interventions - pulmonary edema - management

Kernaussagen

• Innerhalb der letzten 20 Jahre konnten wesentliche Fortschritte im Verständnis der pathophysiologischen Vorgänge des akuten Lungenversagens und der Auswirkungen einer mechanischen Beatmung erzielt werden.

• Innerhalb der letzten Dekade wurden unterschiedliche Strategien zur Behandlung des akuten Lungenversagens in multizentrischen, randomisierten, kontrollierten Untersuchungen evaluiert.

• Für die untersuchten Patientengruppen mit akutem Lungenversagen zeigte keine dieser Strategien hinsichtlich des finalen Outcomeparameters „Mortalität” einen Vorteil.

• Keine der dargestellten Strategien wird derzeit als Routineverfahren für die Behandlung des akuten Lungenversagens empfohlen.

• Einzelne Strategien konnten bei Patienten mit akutem Lungenversagen die Anzahl beatmungsfreier Tage erhöhen und die Anzahl der Intensivtage verringern. Dies könnte die Behandlungskosten von ARDS–Patienten reduzieren.

• Die Therapiestrategien konnten zwar in den untersuchten Patientengruppen keinen Vorteil erzielen; die negativen Ergebnisse der Studien bedeuten aber nicht notwendigerweise, dass diese Strategien komplett ineffektiv sind.

• Die Gründe für die negativen Ergebnisse der klinischen Untersuchungen sind multifaktoriell: z.B. Translation experimenteller Bedingungen in eine klinische Situation, Heterogenität der untersuchten Patientengruppen.

• Neue pharmakologische Strategien werden derzeit experimentell und klinisch evaluiert und das Studiendesign zukünftiger Untersuchungen wird kritisch überdacht hinsichtlich modifizierte Endpunkte und differenziertere Patientenauswahl (z.B. extrapulmonales vs. pulmonales Lungenversagen).

Literatur

• 1 Pratt PC, Vollmer RT, Shelburne JD, Crapo JD.. Pulmonary morphology in a multihospital collaborative extracorporeal membrane oxygenation project. I. Light microscopy.  Am J Pathol. 1979;  95 191-214
• 2 Bachofen M, Weibel ER.. Structural alterations of lung parenchyma the adult respiratory distress syndrome.  Clin Chest Med. 1982;  3 35-56
• 3 Bernard GR, Artigas A, Brigham KL. et al. . 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
• 4 Wiegers GJ, Reul JM. Induction of cytokine receptors by glucocorticoids: functional and pathologigal significance.  Trends Pharmacol Sci. 1998;  19 317-321
• 5 Newton R.. Molecular mechanisms of glucocorticoid action: what is important?.  Thorax. 2000;  55 603-615
• 6 Saatcioglu F, Claret FX, Karin M.. Negative transcriptional regulation by nuclear receptors.  Semin Cancer Biol. 1994;  5 347-359
• 7 van de Stolpe A, Caldenhoven E, Raaijmakres JA. et al. . Glucocorticoid mediated repression of intercellular adhesion molecule–1 expression in human monocytic and bronchial epithelial cell lines.  Am J Respir Cell Mol Biol. 1993;  8 340-347
• 8 Thompson BT.. Glucocorticoids and acute lung injury.  Crit Care Med.. 2003;  31
• 9 Dik WA, McAnulty RJ, Versnel MA. et al. . Short course dexamethasone treatment following injury inhibits bleomycin induced fibrosis in rats.  Thorax. 2003;  58 765-771
• 10 Sprung CL, Caralis PV, Marcial EH. et al. . The effects of high–dose corticosteroids in patients with septic shock. A prospective, controlled study.  N Engl J Med. 1984;  311 1137-1143
• 11 Weigelt JA, Norcross JF, Borman KR. et al. . Early steroid therapy for respiratory failure.  Arch Surg. 1985;  120 536-540
• 12 Bone RC, Fisher Jr CJ, Clemmer TP. et al. . Early methylprednisolone treatment for septic syndrome and the adult respiratory distress syndrome.  Chest. 1987;  92 1032-1036
• 13 Luce JM, Montgomery AB, Marks JD. et al. . Ineffectiveness of high–dose methylprednisolone in preventing parenchymal lung injury and improving mortality in patients with septic shock.  Am Rev Respir Dis. 1988;  138 62-68
• 14 Bernard GR, Luce JM, Sprung CL. et al. . High–dose corticosteroids in patients with the adult respiratory distress syndrome.  N Engl J Med. 1987;  317 1565-1570
• 15 The Acute Respiratory Distress Syndrome Network. . Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome.  N Engl J Med. 2006;  354 1671-1684
• 16 Williams JG, Maier RV.. Ketoconazole inhibits alveolar macrophage production of inflammatory mediators involved in acute lung injury (adult respiratory distress syndrome).  Surgery. 1992;  112 270-277
• 17 Lelcuk S, Huval WV, Valeri CR. et al. . Inhibition of ischemiainduced thromboxane synthesis in man.  J Trauma. 1984;  24 393-396
• 18 Ketoconazole for early treatment of acute lung injury and acute respiratory distress syndrome: a randomized controlled trial. The ARDS Network.  JAMA. 2000;  283 1995-2002
• 19 Bursten SL, Federighi DA, Parsons P. et al. . An increase in serum C18 unsaturated free fatty acids as a predictor of the development of acute respiratory distress syndrome.  Crit Care Med. 1996;  24 1129-1136
• 20 Welsh CH, Lien D, Worthen GS. et al. . Pentoxifylline decreases endotoxin–induced pulmonary neutrophil sequestration and extravascular protein accumulation in the dog.  Am Rev Respir Dis. 1988;  138 1106-1114
• 21 Seear MD, Hannam VL, Kaapa P. et al. . Effect of pentoxifylline on hemodynamics, alveolar fluid reabsorption, and pulmonary edema in a model of acute lung injury.  Am Rev Respir Dis. 1990;  142 1083-1087
• 22 Randomized, placebo–controlled trial of lisofylline for early treatment of acute lung injury and acute respiratory distress syndrome.  Crit Care Med. 2002;  30 1-6
• 23 Baird BR, Cheronis JC, Sandhaus RA. et al. . O2 metabolites and neutrophil elastase synergistically cause edematous injury in isolated rat lungs.  J Appl Physiol. 1986;  61 2224-2229
• 24 Pacht ER, Timerman AP, Lykens MG. et al. . Deficiency of alveolar fluid glutathione in patients with sepsis and the adult respiratory distress syndrome.  Chest. 1991;  100 1397-1403
• 25 Bernard GR.. N–acetylcysteine in experimental and clinical acute lung injury.  Am J Med.. 1991;  91
• 26 Walsh TS, Lee A.. N–acetylcysteine administration in the critically ill.  Intensive Care Med. 1999;  25 432-434
• 27 Ware LB, Matthay MA.. The acute respiratory distress syndrome.  N Engl J Med. 2000;  342 1334-1349
• 28 Moran LK, Gutteridge JM, Quinlan GJ.. Thiols in cellular redox signalling and control.  Curr Med Chem. 2001;  8 763-772
• 29 Quinlan GJ, Evans TW, Gutteridge JM.. Oxidative damage to plasma proteins in adult respiratory distress syndrome.  Free Radic Res. 1994;  20 289-298
• 30 Finfer S, Norton R, Bellomo R. et al. . The SAFE study: saline vs. albumin for fluid resuscitation in the critically ill.  Vox Sang.. 2004;  87 123-131
• 31 Wright JR.. Immunoregulatory functions of surfactant proteins.  Nat Rev Immunol. 2005;  5 58-68
• 32 Albert RK, Lakshminarayan S, Hildebrandt J. et al. . Increased surface tension favors pulmonary edema formation in anesthetized dogs lungs.  J Clin Invest. 1979;  63 1015-1018
• 33 Anzueto A, Baughman RP, Guntupalli KK. et al. . Aerosolized surfactant in adults with sepsis–induced acute respiratory distress syndrome: Exosurf Acute Respiratory Distress Syndrome Sepsis Study Group.  N Engl J Med. 1996;  334 1417-1421
• 34 Spragg RG, Lewis JF, Wurst W. et al. . Treatment of acute respiratory distress syndrome with recombinant surfactant protein C surfactant.  Am J Respir Crit Care Med. 2003;  167 1562-1566
• 35 Spragg RG, Lewis JF, Walmrath HD. et al. . Effect of recombinant surfactant protein C–based surfactant on the acute respiratory distress syndrome.  N Engl J Med. 2004;  351 884-892
• 36 Kaisers U, Busch T, Deja M. et al. . Selective pulmonary vasodilation in acute respiratory distress syndrome.  Crit Care Med.. 2003;  31 337-342
• 37 Rossaint R, Falke KJ, Lopez F. et al. . Inhaled nitric oxide for the adult respiratory distress syndrome.  N Engl J Med. 1993;  328 399-405
• 38 Pepke–Zaba J, Higenbottam TW, Dinh–Xuan AT. et al. . Inhaled nitric oxide as a cause of selective pulmonary vasodilatation in pulmonary hypertension.  Lancet. 1991;  338 1173-1174
• 39 Lundin S, Mang H, Smithies M. et al. . Inhalation of nitric oxide in acute lung injury: results of a European multicentre study. The European Study Group of Inhaled Nitric Oxide.  Intensive Care Med. 1999;  25 911-919
• 40 Dellinger RP, Zimmerman JL, Taylor RW. et al. . 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
• 41 Meyer J, Theilmeier G, Van Aken H. et al. . Inhaled prostaglandin E1 for treatment of acute lung injury in severe multiple organ failure.  Anesth Analg. 1988;  86 753-758
• 42 Abraham E, Baughman R, Fletcher E. et al. . Liposomal prostaglandin E1 (TLC C–53) in acute respiratory distress syndrome: a controlled randomized, double–blind, multi–center clinical trial.  Crit Care Med. 1999;  27 1478-1485
• 43 Ware LB, Matthay MA.. Alveolar fluid clearance is impaired in the majority of patients with acute lung injury and the acute respiratory distress syndrome.  Am J Respir Crit Care Med. 2001;  163 1376-1383
• 44 Widdicombe JH.. How does cAMP increase active Na absorption across alveolar epithelium?.  Am J Physiol Lung Cell Mol Physiol. 2000;  278 231-232
• 45 Dobbs LG, Gonzalez R, Matthay MA. et al. . Highly water–permeable type I alveolar epithelial cells confer high water permeability between the airspace and vasculature in rat lung.  Proc Natl Acad Sci U S A. 1998;  95 2991-2996
• 46 Saldias FJ, Lecuona E, Comellas AP. et al. . Beta–adrenergic stimulation restores rat lung ability to clear edema in ventilator–associated lung injury.  Am J Respir Crit Care Med. 2000;  162 282-287
• 47 Crandall ED, Matthay MA.. Alveolar epithelial transport.Basic science to clinical medicine.  Am J Respir Crit Care Med. 2001;  163 1021-1029
• 48 Matthay MA, Folkesson HG, Clerici C.. Lung epithelial fluid transport and the resolution of pulmonary edema.  Physiol Rev. 2002;  82 569-600
• 49 Sakuma T, Okaniwa G, Nakada T. et al. . Alveolar fluid clearance in the resected human lung.  AmJ Respir Crit Care Med. 1994;  150 305-310
• 50 Zhang H, Kim YK, Govindarajan A. et al. . Effect of adrenoreceptors on endotoxin–induced cytokines and lipid peroxidation in lung explants.  Am J Respir Crit Care Med. 1999;  160 1703-1710
• 51 Minnear FL, DeMichele MA, Leonhardt S. et al. . Isoproterenol antagonizes endothelial permeability induced by thrombin and thrombin receptor peptide.  J Appl Physiol. 1993;  75 1171-1179
• 52 Perkins GD, McAuley DF, Thickett DR. et al. . The ß–Agonist Lung Injury Trial (BALTI): a randomized placebo–controlled clinical trial.  Am J Respir Crit Care Med. 2006;  173 281-287
• 53 Idell S, Peters J, James KK. et al. . Local abnormalities of coagulation and fibrinolytic pathways that promote alveolar fibrin deposition in the lungs of baboons with diffuse alveolar damage.  J Clin Invest. 1989;  84 181-193
• 54 Yi ES, Salgado M, Williams S. et al. . Keratinocyte growth factor decreases pulmonary edema, transforming growth factor–beta and platelet–derived growth factor–BB expression, and alveolar type II cell loss in bleomycin–induced lung injury.  Inflammation. 1998;  22 315-325
• 55 Yano T, Deterding RR, Simonet WS. et al. . Keratinocyte growth factor reduces lung damage due to acid instillation in rats.  Am J Respir Cell Mol Biol. 1996;  15 433-442
• 56 Sugahara K, Iyama K, Kuroda MJ. et al. . Double intratracheal instillation of keratinocyte growth factor prevents bleomycininduced lung fibrosis in rats.  J Pathol. 1998;  186 90-98
• 57 Mason CM, Guery BP, Summer WR. et al. . Keratinocyte growth factor attenuates lung leak induced by alphanaphthylthiourea in rats.  Crit Care Med. 1996;  24 925-931
• 58 Guery BP, Mason CM, Dobard EP. et al. . Keratinocyte growth factor increases transalveolar sodium reabsorption in normal and injured rat lungs.  Am J Respir Crit Care Med. 1997;  155 1777-1784
• 59 Weber H, Taylor DS, Molloy CJ.. Angiotensin II induces delayed mitogenesis and cellular proliferation in rat aortic smooth muscle cells. Correlation with the expression of specific endogenous growth factors and reversal by suramin.  J Clin Invest. 1994;  93 788-798
• 60 Marshall RP, Gohlke P, Chambers RC. et al. . Angiotensin II and the fibroproliferative response to acute lung injury.  Am J Physiol Lung Cell Mol Physiol.. 2004;  286
• 61 Negri EM, Hoelz C, Barbas CS. et al. . Acute remodeling of parenchyma in pulmonary and extrapulmonary ARDS. An autopsy study of collagen–elastic system fibers.  Pathol Res Pract. 2002;  198 355-361
• 62 Ward WF, Molteni A, Ts'ao CH. et al. . Radiation pneumotoxicity in rats: modification by inhibitors of angiotensin converting enzyme.  Int J Radiat Oncol Biol Phys. 1992;  22 623-625
• 63 Wang R, Zagariya A, Ibarra–Sunga O. et al. . Angiotensin II induces apoptosis in human and rat alveolar epithelial cells.  Am J Physiol. 1999;  276
• 64 Sibbald WJ, Short AK, Warshawski FJ. et al. . Thermal dye measurements of extravascular lung water in critically ill patients: intravascular Starling forces and extravascular lung water in the adult respiratory distress syndrome.  Chest. 1985;  87 585-92
• 65 Ware LB, Matthay MA.. The acute respiratory distress syndrome.  N Engl J Med. 2000;  342 1334-49
• 66 Acute Respiratory Distress Syndrome Network. . Comparison of two fluid–management strategies in acute lung injury.  N Engl J Med. 2006;  354 2564-2575
• 67 Acute Respiratory Distress Syndrome Network. . Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome.  N Engl J Med. 2000;  342 1301-1308
• 68 Rivers EP.. Fluid–management strategies in acute lung injury: liberal, conservative, or both?.  N Engl J Med. 2006;  354 2564-2575
• 69 Leal RP, Gonzalez R, Gaona C. et al. .Randomized trial compare prone vs supine position in patients with ARDS (abstract). Am J Respir Crit Care Med1997; 155: A 745
• 70 Gattinoni L, Tognoni G, Pesenti A. et al. . Effect of prone positioning on the survival of patients with acute respiratory failure.  N Engl J Med. 2001;  345 568-573
• 71 Beuret P, Carton MJ, Nourdine K. et al. . Prone position as prevention of lung injury in comatose patients: a prospective, randomized, controlled study.  Intensive Care Med. 2002;  28 564-569
• 72 Chan MC, Hsu JY, Liu HH. et al. . Effects of prone position on inflammatory markers in patients with ARDS due to community–acquired pneumonia.  J Formos Med Assoc. 2007;  106 708-716
• 73 Beuret P, Carton MJ, Nourdine K. et al. . Prone position as prevention of lung injury in comatose patients: a prospective, randomized, controlled study.  Intensive Care Med. 2002;  28 564-569
• 74 Mancebo J, Fernandez R, Blanch L. et al. . A multicenter trial of prolonged prone ventilation in severe acute respiratory distress syndrome.  Am J Respir Crit Care Med. 2006;  173 1233-1239
• 75 Demory D, Michelet P, Arnal JM. et al. . High–frequency oscillatory ventilation following prone positioning prevents a further impairment in oxygenation.  Crit Care Med. 2007;  35 106-111
• 76 Sud S, Sud M, Friedrich JO, Adhikari NK.. Effect of mechanical ventilation in the prone position on clinical outcomes in patients with acute hypoxemic respiratory failure: a systematic review and analysis.  CMAJ. 2008;  178 1153-1161
• 77 Abeoug F, Quanes–Besbes L, Elatrous S, Brochard L.. The effect of prone positioning in acute respiratory distress syndrome or acute lung injury: a meta–analysis. Areas of uncertainity and recommendations for research.  Intensive Care Med.. 2008;  19
• 78 Lagerungstherapie bei pulmonalen Funktionsstörungen. S2e–Leitlinie der deutschen Gesellschaft für Anästhesiologie und Intensivmedizin (DGAI).  Anaesth Intensivmed. 2008;  49
• 79 Zapol WM, Snider MT, Hill JD. et al. . Extracorporeal membrane oxygenation in severe acute respiratory failure: a randomized prospective study.  JAMA. 1979;  242 2193-2196
• 80 Morris AH, Wallace CJ, Menlove RL. et al. . Randomized clinical trial of pressure–controlled inverse ratio ventilation and extracorporeal CO2 removal for adult respiratory distress syndrome.  Am J Respir Crit Care Med. 1994;  149 295-305