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Treatments in Respiratory Medicine

, Volume 3, Issue 5, pp 307–328 | Cite as

Pharmacologic Treatments for Acute Respiratory Distress Syndrome and Acute Lung Injury

Systematic Review and Meta-Analysis
  • Neill AdhikariEmail author
  • Karen E. A. Burns
  • Maureen O. Meade
Original Research Article

Abstract

Background: Multiple pharmacologic treatments have been studied for patients with acute respiratory distress syndrome (ARDS) and acute lung injury (ALI). Our objective was to systematically evaluate this literature to determine the effects of these interventions on important clinical outcomes.

Methods: We searched OVID versions of CENTRAL (The Cochrane Library Issue 3, 2003), MEDLINE (1966-week 2, January 2004), EMBASE (1980-week 4, 2004), CINAHL (1982-week 2, January 2004), and HEALTHSTAR (1995-December 2003); proceedings from four conferences (1994–2003); and bibliographies of review articles and included studies. We included randomized controlled trials (RCTs) of pharmacologic treatments compared with no therapy or placebo for established ARDS and ALI in adults admitted to an intensive care unit, with measurement of early mortality, late mortality, duration of ventilation, ventilator-free days, non-pulmonary organ dysfunction, or adverse events. We excluded trials in other populations incorporating subgroup analyses of patients with ARDS and ALI and studies of nitric oxide, partial liquid ventilation, and fluid and nutritional interventions. Two reviewers independently screened studies and abstracted data from studies included in the analysis. Data were pooled using random effects models where appropriate.

Results: We retrieved 75 potentially relevant articles and abstracts, of which 33 trials randomizing 3272 patients met our selection criteria. Meta-analysis showed no effect on early mortality for alprostadil ([prostaglandin E1] seven studies; 693 patients; relative risk [RR] 0.95; 95% confidence interval [CI], 0.77, 1.17), acetylcysteine (five studies; 235 patients; RR 0.89; 95% CI, 0.65, 1.21), early high-dose corticosteroids (two studies; 180 patients; RR 1.12; 95% CI, 0.72, 1.74), or surfactant therapy (nine studies; 1418 patients; RR 0.93; 95% CI, 0.77, 1.12). Most trials of alprostadil, early high-dose corticosteroids, and surfactant therapy showed more adverse events in the active therapy arm. Single small RCTs demonstrated lower hospital mortality (24 patients, RR 0.20; 95% CI, 0.05, 0.81) with corticosteroids for late phase ARDS and lower 1-month mortality (30 patients, RR 0.67; 95% CI, 0.47, 0.95) with pentoxifylline for patients with metastatic cancer and ARDS. Individual trials of nine additional interventions failed to show beneficial effects on prespecified outcomes.

Conclusions: Effective pharmacotherapy for ARDS is extremely limited. Corticosteroids for late phase ARDS and pentoxifylline for patients with metastatic cancer and ARDS reduced mortality in single small studies. However, further research is required to investigate their potential benefit in the treatment of ALI/ARDS.

Keywords

Acute Lung Injury Acute Respiratory Distress Syndrome Pentoxifylline Early Mortality Acetylcysteine 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgment

The authors thank Elizabeth Uleryk for assistance in searching bibliographic databases, Dr Jan Friedrich and Dr Yumiko Imai for assistance in translation, and Dr Deirdre Grady for assistance in searching conference proceedings.

This study received no funding. Dr Meade is a Peter Lougheed Scholar of the Canadian Institutes of Health Research. Dr Burns holds a postdoctoral fellowship from Merck Frosst and the Canadian Lung Association. The authors have no conflicts of interest that are directly relevant to the content of this study.

References

  1. 1.
    Ashbaugh DG, Bigelow DB, Petty TL, et al. Acute respiratory distress in adults. Lancet 1967 Aug 12; 2: 319–23PubMedCrossRefGoogle Scholar
  2. 2.
    Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J Med 2000 May 4; 342: 1334–49PubMedCrossRefGoogle Scholar
  3. 3.
    Bernard GR, Artigas A, Brigham KL, et al. Report of the American-European consensus conference on ARDS: definitions, mechanisms, relevant outcomes and clinical trial coordination. The Consensus Committee. Intensive Care Med 1994; 20: 225–32PubMedCrossRefGoogle Scholar
  4. 4.
    Herridge MS, Cheung AM, Tansey CM, et al. One-year outcomes in survivors of the acute respiratory distress syndrome. N Engl J Med 2003 Feb 20; 348: 683–93PubMedCrossRefGoogle Scholar
  5. 5.
    Dos Santos CC, Slutsky AS. Invited review: mechanisms of ventilator-induced lung injury: a perspective. J Appl Physiol 2000 Oct; 89: 1645–55PubMedGoogle Scholar
  6. 6.
    Murphy DB, Cregg N, Tremblay L, et al. Adverse ventilatory strategy causes pulmonary-to-systemic translocation of endotoxin. Am J Respir Crit Care Med 2000 Jul; 162: 27–33PubMedGoogle Scholar
  7. 7.
    Ranieri VM, Suter PM, Tortorella C, et al. Effect of mechanical ventilation on inflammatory mediators in patients with acute respiratory distress syndrome: a randomized controlled trial. JAMA 1999 Jul 7; 282: 54–61PubMedCrossRefGoogle Scholar
  8. 8.
    The 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 May 4; 342: 1301–8CrossRefGoogle Scholar
  9. 9.
    Stewart TE, Meade MO, Cook DJ, et al. Evaluation of a ventilation strategy to prevent barotrauma in patients at high risk for acute respiratory distress syndrome: Pressure- and Volume-Limited Ventilation Strategy Group. N Engl J Med 1998 Feb 5; 338: 355–61PubMedCrossRefGoogle Scholar
  10. 10.
    Brower RG, Shanholtz CB, Fessier HE, et al. Prospective, randomized, controlled clinical trial comparing traditional versus reduced tidal volume ventilation in acute respiratory distress syndrome patients. Crit Care Med 1999 Aug; 27: 1492–8PubMedCrossRefGoogle Scholar
  11. 11.
    Brochard L, Roudot-Thoraval F, Roupie E, et al. Tidal volume reduction for prevention of ventilator-induced lung injury in acute respiratory distress syndrome: the Multicenter Trial Group on Tidal Volume reduction in ARDS. Am J Respir Crit Care Med 1998 Dec; 158: 1831–8PubMedGoogle Scholar
  12. 12.
    Amato MB, Barbas CS, Medeiros DM, et al. Effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome. N Engl J Med 1998 Feb 5; 338: 347–54PubMedCrossRefGoogle Scholar
  13. 13.
    Petrucci N, Iacovelli W. Ventilation with lower tidal volumes versus traditional tidal volumes in adults for acute lung injury and acute respiratory distress syndrome. Cochrane Database Syst Rev 2004; (2): CD003844Google Scholar
  14. 14.
    Luce JM. Acute lung injury and the acute respiratory distress syndrome. Crit Care Med 1998 Feb; 26: 369–76PubMedCrossRefGoogle Scholar
  15. 15.
    Sokol J, Jacobs SE, Bohn D. Inhaled nitric oxide for acute hypoxemic respiratory failure in children and adults. Cochrane Database Syst Rev 2003; (1): CD002787Google Scholar
  16. 16.
    Taylor RW, Zimmerman JL, Dellinger RP, et al. Low-dose inhaled nitric oxide in patients with acute lung injury: a randomized controlled trial. JAMA 2004 Apr 7; 291: 1603–9PubMedCrossRefGoogle Scholar
  17. 17.
    Adhikari N, Burns KEA, Meade MO. Pharmacologic therapies for adults with acute lung injury and acute respiratory distress syndrome. Cochrane Database Syst Rev 2004; (4): CD004477Google Scholar
  18. 18.
    Schoenfeld DA, Bernard GR. Statistical evaluation of ventilator-free days as an efficacy measure in clinical trials of treatments for acute respiratory distress syndrome. Crit Care Med 2002 Aug; 30: 1772–7PubMedCrossRefGoogle Scholar
  19. 19.
    Oxman AD, Guyatt GH. A consumer’s guide to subgroup analyses. Ann Intern Med 1992 Jan 1; 116: 78–84PubMedGoogle Scholar
  20. 20.
    Robinson KA, Dickersin K. Development of a highly sensitive search strategy for the retrieval of reports of controlled trials using PubMed. Int J Epidemiol 2002 Feb; 31: 150–3PubMedCrossRefGoogle Scholar
  21. 21.
    Bernard GR. Potential of N-acetylcysteine as treatment for the adult respiratory distress syndrome. Eur Respir J Suppl 1990 Oct; 11: 496s–8sPubMedGoogle Scholar
  22. 22.
    Bernard GR. N-acetylcysteine in experimental and clinical acute lung injury. Am J Med 1991 Sep 30; 91: 54S–9SPubMedCrossRefGoogle Scholar
  23. 23.
    Conner BD, Bernard GR. Acute respiratory distress syndrome: potential pharmacologic interventions. Clin Chest Med 2000 Sep; 21: 563–87PubMedCrossRefGoogle Scholar
  24. 24.
    McIntyre Jr RC, Pulido EJ, Bensard DD, et al. Thirty years of clinical trials in acute respiratory distress syndrome. Crit Care Med 2000 Sep; 28: 3314–31PubMedCrossRefGoogle Scholar
  25. 25.
    Que LG, Huang Y-C. Pharmacologic adjuncts during mechanical ventilation. Semin Respir Crit Care Med 2000; 21: 223–32PubMedCrossRefGoogle Scholar
  26. 26.
    Spragg RG. Surfactant replacement therapy. Clin Chest Med 2000 Sep; 21: 531–41PubMedCrossRefGoogle Scholar
  27. 27.
    Brower RG, Ware LB, Berthiaume Y, et al. Treatment of ARDS. Chest 2001 Oct; 120: 1347–67PubMedCrossRefGoogle Scholar
  28. 28.
    Anzueto A. Surfactant supplementation in the lung. Respir Care Clin N Am 2002 Jun;8: 211–36PubMedCrossRefGoogle Scholar
  29. 29.
    Chadda K, Annane D. The use of corticosteroids in severe sepsis and acute respiratory distress syndrome. Ann Med 2002; 34: 582–9PubMedCrossRefGoogle Scholar
  30. 30.
    Cranshaw J, Griffiths MJ, Evans TW. The pulmonary physician in critical care part 9: non-ventilatory strategies in ARDS. Thorax 2002 Sep; 57: 823–9PubMedCrossRefGoogle Scholar
  31. 31.
    Dos Santos CC, Chant C, Slutsky AS. Pharmacotherapy of acute respiratory distress syndrome. Expert Opin Pharmacother 2002; 3: 875–88PubMedCrossRefGoogle Scholar
  32. 32.
    Spragg RG. The future of surfactant therapy for patients with acute lung injury: new requirements and new surfactants. Biol Neonate 2002; 81: 20–4PubMedCrossRefGoogle Scholar
  33. 33.
    Tasaka S, Hasegawa N, Ishizaka A. Pharmacology of acute lung injury. Pulm Pharmacol Ther 2002; 15: 83–95PubMedCrossRefGoogle Scholar
  34. 34.
    Laterre PF, Wittebole X, Dhainaut JF. Anticoagulant therapy in acute lung injury. Crit Care Med 2003 Apr; 31: S329–36PubMedCrossRefGoogle Scholar
  35. 35.
    Lewis JF, Brackenbury A. Role of exogenous surfactant in acute lung injury. Crit Care Med 2003 Apr; 31: S324–8PubMedCrossRefGoogle Scholar
  36. 36.
    Lovat R, Preiser J-C. Antioxidant therapy in intensive care. Curr Opin Crit Care 2003; 9: 266–70PubMedCrossRefGoogle Scholar
  37. 37.
    Thompson BT. Glucocorticoids and acute lung injury. Crit Care Med 2003 Apr; 31: S253–7PubMedCrossRefGoogle Scholar
  38. 38.
    Wiedemann HP, Arroliga AC, Komara Jr JJ. Emerging systemic pharmocologic approaches in acute respiratory distress syndrome. Respir Care Clin N Am 2003; 9: 419–35PubMedCrossRefGoogle Scholar
  39. 39.
    Spragg RG, Lewis JF, Walmrath H-D, et al. Effect of recombinant surfactant protein C-based surfactant on the acute respiratory distress syndrome. N Engl J Med 2004 Aug 26; 351(9): 884–92PubMedCrossRefGoogle Scholar
  40. 40.
    Weg JG, Balk RA, Tharratt RS, et al. Safety and potential efficacy of an aerosolized surfactant in human sepsis-induced adult respiratory distress syndrome. JAMA 1994 Nov 9; 272: 1433–8PubMedCrossRefGoogle Scholar
  41. 41.
    Vincent JL, Brase R, Santman F, et al. A multi-centre, double-blind, placebo-controlled study of liposomal prostaglandin E1 (TLC C-53) in patients with acute respiratory distress syndrome. Intensive Care Med 2001 Oct; 27: 1578–83PubMedCrossRefGoogle Scholar
  42. 42.
    Gregory TJ, Steinberg KP, Spragg R, et al. Bovine surfactant therapy for patients with acute respiratory distress syndrome. Am J Respir Crit Care Med 1997 Apr; 155: 1309–15PubMedGoogle Scholar
  43. 43.
    DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986 Sep; 7: 177–88PubMedCrossRefGoogle Scholar
  44. 44.
    Cochran W. The combination of estimates from different experiments. Biometrics 1954; 10: 101–29CrossRefGoogle Scholar
  45. 45.
    van der Merwe CJ, Louw AF, Welthagen D, et al. Adult respiratory distress syndrome in cases of severe trauma: the prophylactic value of methylprednisolone sodium succinate. S Afr Med J 1985 Feb 23; 67: 279–84PubMedGoogle Scholar
  46. 46.
    Kawai S, Kawahira M, Miura H, et al. Effect of ulinastatin on septic ARDS. Japanese Pharmacol Ther 1988 Aug; 16: 453–9Google Scholar
  47. 47.
    Kawai S, Sakayori S, Watanabe H, et al. Usefulness of a protease inhibitor (urinastatin) in ARDS with infectious diseases. Nihon Kyobu Shikkan Gakkai Zasshi 1990 Jun; 28: 843–51PubMedGoogle Scholar
  48. 48.
    Russell JA, Ronco JJ, Dodek PM. Physiologic effects and side effects of prostaglandin E1 in the adult respiratory distress syndrome. Chest 1990 Mar; 97: 684–92PubMedCrossRefGoogle Scholar
  49. 49.
    Radermacher P, Huet Y, Pluskwa F, et al. Comparison of ketanserin and sodium nitroprusside in patients with severe ARDS. Anesthesiology 1988 Jan; 68: 152–7PubMedCrossRefGoogle Scholar
  50. 50.
    Radermacher P, Santak B, Falke KJ. Comparison of prostaglandin E1 and nitroglycerin in patients with ARDS. Prog Clin Biol Res 1989; 301: 267–70PubMedGoogle Scholar
  51. 51.
    Lucas CE, Ledgerwood AM. Pulmonary response of massive steroids in seriously injured patients. Ann Surg 1981 Sep; 194: 256–61PubMedCrossRefGoogle Scholar
  52. 52.
    Umberger R, Headley A, Waters T, et al. Cost-effectiveness of methylprednisolone treatment (MPT) in unresolving ARDS (U-ARDS) [abstract]. Am J Respir Crit Care Med 2002; 165: A22Google Scholar
  53. 53.
    Ogawa M, Tamakuma S, Hirasawa H, et al. Effect of a specific neutrophil elastase inhibitor, ONO-5046 Na on the lung dysfunction associated with SIRS (systemic inflammatory response syndrome) [abstract]. Eur Respir J 1996; 9: 286sGoogle Scholar
  54. 54.
    Bone RC, Fisher Jr CJ, Clemmer TP, et al. Early methylprednisolone treatment for septic syndrome and the adult respiratory distress syndrome. Chest 1987 Dec; 92: 1032–6PubMedCrossRefGoogle Scholar
  55. 55.
    Nelson S, Belknap SM, Carlson RW, et al. A randomized controlled trial of filgrastim as an adjunct to antibiotics for treatment of hospitalized patients with community-acquired pneumonia: CAP Study Group. J Infect Dis 1998 Oct; 178: 1075–80PubMedCrossRefGoogle Scholar
  56. 56.
    Nelson S, Heyder AM, Stone J, et al. A randomized controlled trial of filgrastim for the treatment of hospitalized patients with multilobar pneumonia. J Infect Dis 2000; 182: 970–3PubMedCrossRefGoogle Scholar
  57. 57.
    Tuxen DV, Cade JF. Effect of aprotinin in adult respiratory distress syndrome. Anaesth Intensive Care 1986 Nov; 14: 390–9PubMedGoogle Scholar
  58. 58.
    Vincent JL, Brimioulle S, Berre J, et al. Prevention of the adult respiratory distress syndrome with dipyridamole. Crit Care Med 1985 Oct; 13: 783–5PubMedCrossRefGoogle Scholar
  59. 59.
    Yu M, Tomasa G. A double-blind, prospective, randomized trial of ketoconazole, a thromboxane synthetase inhibitor, in the prophylaxis of the adult respiratory distress syndrome. Crit Care Med 1993 Nov; 21: 1635–42PubMedCrossRefGoogle Scholar
  60. 60.
    Schuster DP, Metzler M, Opal S, et al. Recombinant platelet-activating factor acetylhydrolase to prevent acute respiratory distress syndrome and mortality in severe sepsis: phase IIb, multicenter, randomized, placebo-controlled, clinical trial. Crit Care Med 2003 Jun; 31: 1612–9PubMedCrossRefGoogle Scholar
  61. 61.
    Slotman GJ, Burchard KW, D’Arezzo A, et al. Ketoconazole prevents acute respiratory failure in critically ill surgical patients. J Trauma 1988 May; 28: 648–54PubMedCrossRefGoogle Scholar
  62. 62.
    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 Jul; 24: 1129–36PubMedCrossRefGoogle Scholar
  63. 63.
    McMichan JC, Rosengarten DS, McNeur JC, et al. Posttraumatic lung syndrome: definition, diagnosis, and therapy: report of a double blind study. Med Welt 1976 Nov 26; 76: 2331–40PubMedGoogle Scholar
  64. 64.
    Luce JM, Montgomery AB, Marks JD, et al. Ineffectiveness of high-dose methyl-prednisolone in preventing parenchymal lung injury and improving mortality in patients with septic shock. Am Rev Respir Dis 1988 Jul; 138: 62–8PubMedCrossRefGoogle Scholar
  65. 65.
    McMichan JC, Rosengarten DS, Philipp E. Prophylaxis of post-traumatic pulmonary insufficiency by protease-inhibitor therapy with aprotinin: a clinical study. Circ Shock 1982 Feb; 9: 107–16PubMedGoogle Scholar
  66. 66.
    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 Nov 1; 311: 1137–43PubMedCrossRefGoogle Scholar
  67. 67.
    Fourrier F, Chopin C, Huart JJ, et al. Double-blind, placebo-controlled trial of antithrombin III concentrates in septic shock with disseminated intravascular coagulation. Chest 1993 Sep; 104: 882–8PubMedCrossRefGoogle Scholar
  68. 68.
    Tanaka H, Nishino M, Nakamori Y, et al. Granulocyte colony-stimulating factor (G-CSF) stiffens leukocytes but attenuates inflammatory response without lung injury in septic patients. J Trauma 2001 Dec; 51: 1110–6PubMedCrossRefGoogle Scholar
  69. 69.
    Wunderink R, Leeper Jr K, Schein R, et al. Filgrastim in patients with pneumonia and severe sepsis or septic shock. Chest 2001 Feb; 119: 523–9PubMedCrossRefGoogle Scholar
  70. 70.
    Bernard GR, Reines HD, Halushka PV, et al. Prostacyclin and thromboxane A2 formation is increased in human sepsis syndrome: effects of cyclooxygenase inhibition. Am Rev Respir Dis 1991 Nov; 144: 1095–101PubMedCrossRefGoogle Scholar
  71. 71.
    Konrad F, Schoenberg MH, Wiedmann H, et al. The application of N-acetylcysteine as an antioxidant and mucolytic in mechanical ventilation in intensive care patients: a prospective, randomized, placebo-controlled, double-blind study. Anaesthesist 1995 Sep; 44: 651–8PubMedCrossRefGoogle Scholar
  72. 72.
    Looareesuwan S, Wilairatana P, Vannaphan S, et al. Pentoxifylline as an ancillary treatment for severe falciparum malaria in Thailand. Am J Trop Med Hyg 1998 6Mar; 58: 348–53PubMedGoogle Scholar
  73. 73.
    Paran H, Neufeld D, Mayo A, et al. Preliminary report of a prospective randomized study of octreotide in the treatment of severe acute pancreatitis. J Am Coll Surg 1995 Aug; 181: 121–4PubMedGoogle Scholar
  74. 74.
    Paran H, Mayo A, Paran D, et al. Octreotide treatment in patients with severe acute pancreatitis. Dig Dis Sci 2000 Nov; 45: 2247–51PubMedCrossRefGoogle Scholar
  75. 75.
    Satoh D, Matsukawa S, Saishu T, et al. Effect of surfactant on respiratory failure associated with thoracic aneurysm surgery. Crit Care Med 1998 Oct; 26: 1660–2PubMedCrossRefGoogle Scholar
  76. 76.
    Heard SO, Longtine K, Toth I, et al. The influence of liposome-encapsulated prostaglandin E1 on hydrogen peroxide concentrations in the exhaled breath of patients with the acute respiratory distress syndrome. Anesth Analg 1999 Aug; 89: 353–7PubMedGoogle Scholar
  77. 77.
    Bernard GR, Swindell BB, Meredith MJ, et al. Glutathione (GSH) repletion by N-acetylcysteine (NAC) in patients with the adult respiratory distress syndrome [abstract]. Am Rev Respir Dis 1989; 139: A221CrossRefGoogle Scholar
  78. 78.
    Bone RC, Balk RA, Fein AM, et al. A second large controlled clinical study of E5, a monoclonal antibody to endotoxin: results of a prospective, multicenter, randomized, controlled trial. The E5 Sepsis Study Group. Crit Care Med 1995 Jun; 23: 994–1006PubMedCrossRefGoogle Scholar
  79. 79.
    Root RK, Lodato RF, Patrick W, et al. Multicenter, double-blind, placebo-controlled study of the use of filgrastim in patients hospitalized with pneumonia and severe sepsis. Crit Care Med 2003 Feb; 31: 367–73PubMedCrossRefGoogle Scholar
  80. 80.
    Marshall J, for the Afelimomab Study Group. Effect of anti-TNF antibody on pulmonary component of MOD score [abstract]. Am J Respir Crit Care Med 2001 May; 163: A820Google Scholar
  81. 81.
    Bigatello LM, Greene RE, Sprung CL, et al. HA-1A in septic patients with ARDS: results from the pivotal trial. Intensive Care Med 1994 May; 20: 328–34PubMedCrossRefGoogle Scholar
  82. 82.
    Fisher Jr CJ, Dhainaut JF, Opal SM, et al. Recombinant human interleukin 1 receptor antagonist in the treatment of patients with sepsis syndrome: results from a randomized, double-blind, placebo-controlled trial. Phase III rhIL-1ra Sepsis Syndrome Study Group. JAMA 1994 Jun 15; 271: 1836–43PubMedCrossRefGoogle Scholar
  83. 83.
    Bernard GR, Wheeler AP, Russell JA, et al. The effects of ibuprofen on the physiology and survival of patients with sepsis: the Ibuprofen in Sepsis Study Group. N Engl J Med 1997 Mar 27; 336: 912–8PubMedCrossRefGoogle Scholar
  84. 84.
    Shoemaker WC. Effectiveness of prostaglandin E1 in adult respiratory distress syndrome. Prog Clin Biol Res 1987; 236A: 361–8PubMedGoogle Scholar
  85. 85.
    Holcroft JW, Vassar MJ, Weber CJ. Prostaglandin E1 and survival in patients with the adult respiratory distress syndrome: a prospective trial. Semin Respir Med 1986; 7: 40–7Google Scholar
  86. 86.
    Wiedemann H, Baughman R, DeBoisblanc B, et al. A multicenter trial in human sepsis-induced ARDS of an aerosolized synthetic surfactant (Exosurf) [abstract]. Am Rev Respir Dis 1992; 145: A184Google Scholar
  87. 87.
    Slotman GJ, Kerstein MD, Bone RC, et al. The effects of prostaglandin E1 on non-pulmonary organ function during clinical acute respiratory failure: the Prostaglandin E1 Study Group. J Trauma 1992 Apr; 32: 480–8PubMedCrossRefGoogle Scholar
  88. 88.
    Bone RC, Slotman G, Maunder R, et al. Randomized double-blind, multicenter study of prostaglandin E1 in patients with the adult respiratory distress syndrome: Prostaglandin E1 Study Group. Chest 1989 Jul; 96: 114–9PubMedCrossRefGoogle Scholar
  89. 89.
    Bernard GR, Wheeler AP, Arons MM, et al. A trial of antioxidants N-acetylcysteine and procysteine in ARDS: the Antioxidant in ARDS Study Group. Chest 1997 Jul; 112: 164–72PubMedCrossRefGoogle Scholar
  90. 90.
    Ortolani O, Conti A, De Gaudio AR, et al. Protective effects of N-acetylcysteine and rutin on the lipid peroxidation of the lung epithelium during the adult respiratory distress syndrome. Shock 2000 Jan; 13: 14–8PubMedCrossRefGoogle Scholar
  91. 91.
    Holcroft JW, Vassar MJ, Weber CJ. Prostaglandin E1 and survival in patients with the adult respiratory distress syndrome: a prospective trial. Ann Surg 1986 Apr; 203: 371–8PubMedCrossRefGoogle Scholar
  92. 92.
    Rossignon MD, Khayat D, Royer C, et al. Functional and metabolic activity of polymorphonuclear leukocytes from patients with adult respiratory distress syndrome: results of a randomized double-blind placebo-controlled study on the activity of prostaglandin E1. Anesthesiology 1990 Feb; 72: 276–81PubMedCrossRefGoogle Scholar
  93. 93.
    Shoemaker WC, Appel PL. Effects of prostaglandin E1 in adult respiratory distress syndrome. Surgery 1986 Mar; 99: 275–83PubMedGoogle Scholar
  94. 94.
    Abraham E, Park YC, Covington P, et al. Liposomal prostaglandin E1 in acute respiratory distress syndrome: a placebo-controlled, randomized, double-blind, multicenter clinical trial. Crit Care Med 1996 Jan; 24: 10–5PubMedCrossRefGoogle Scholar
  95. 95.
    Abraham E, Baughman R, Fletcher E, et al. Liposomal prostaglandin E1 (TLC C-53) in acute respiratory distress syndrome: a controlled, randomized, double-blind, multicenter clinical trial. TLC C-53 ARDS Study Group. Crit Care Med 1999 Aug; 27: 1478–85PubMedCrossRefGoogle Scholar
  96. 96.
    Jepsen S, Herlevsen P, Knudsen P, et al. Antioxidant treatment with N-acetylcysteine during adult respiratory distress syndrome: a prospective, randomized, placebo-controlled study. Crit Care Med 1992 Jul; 20: 918–23PubMedCrossRefGoogle Scholar
  97. 97.
    Suter PM, Domenighetti G, Schaller MD, et al. N-acetylcysteine enhances recovery from acute lung injury in man: a randomized, double-blind, placebo-controlled clinical study. Chest 1994 Jan; 105: 190–4PubMedCrossRefGoogle Scholar
  98. 98.
    Domenighetti G, Suter PM, Schaller MD, et al. Treatment with N-acetylcysteine during acute respiratory distress syndrome: a randomized, double-blind, placebo-controlled clinical study. J Crit Care 1997 Dec; 12: 177–82PubMedCrossRefGoogle Scholar
  99. 99.
    Weigelt JA, Norcross JF, Borman KR, et al. Early steroid therapy for respiratory failure. Arch Surg 1985 May; 120: 536–40PubMedCrossRefGoogle Scholar
  100. 100.
    Bernard GR, Luce JM, Sprung CL, et al. High-dose corticosteroids in patients with the adult respiratory distress syndrome. N Engl J Med 1987 Dec 17; 317: 1565–70PubMedCrossRefGoogle Scholar
  101. 101.
    Meduri GU, Headley AS, Golden E, et al. Effect of prolonged methylprednisolone therapy in unresolving acute respiratory distress syndrome: a randomized controlled trial. JAMA 1998 Jul 8; 280: 159–65PubMedCrossRefGoogle Scholar
  102. 102.
    Reines HD, Silverman H, Hurst J, et al. Effects of two concentrations of nebulized surfactant (Exosurf) in sepsis-induced adult respiratory distress syndrome (ARDS) [abstract]. Crit Care Med 1992 Apr; 20: S61CrossRefGoogle Scholar
  103. 103.
    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 Jun 1; 167: 1562–6PubMedCrossRefGoogle Scholar
  104. 104.
    Walmrath D, De Vaal JB, Bruining HA, et al. Treatment of ARDS with a recombinant SP-C (rSP-C) based synthetic surfactant [abstract]. Am J Respir Crit Care Med 2000; 161: A379Google Scholar
  105. 105.
    Kesecioglu J, Schultz MJ, Lundberg D, et al. Treatment of acute lung injury (ALI/ARDS) with surfactant [abstract]. Am J Respir Crit Care Med 2001 May; 163: A819Google Scholar
  106. 106.
    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 May 30; 334: 1417–21PubMedCrossRefGoogle Scholar
  107. 107.
    Reines HD, Halushka PV, Olanoff LS, et al. Dazoxiben in human sepsis and adult respiratory distress syndrome. Clin Pharmacol Ther 1985 Apr; 37: 391–5PubMedCrossRefGoogle Scholar
  108. 108.
    Tuxen DV, Wilson JW, Cade JF. Prevention of lower respiratory herpes simplex virus infection with acyclovir in patients with the adult respiratory distress syndrome. Am Rev Respir Dis 1987 Aug; 136: 402–5PubMedCrossRefGoogle Scholar
  109. 109.
    Steinberg SM, Rodriguez JL, Bitzer LG, et al. Indomethacin treatment of human adult respiratory distress syndrome. Circ Shock 1990 Apr; 30: 375–84PubMedGoogle Scholar
  110. 110.
    Ardizzoia A, Lissoni P, Tancini G, et al. Respiratory distress syndrome in patients with advanced cancer treated with pentoxifylline: a randomized study. Support Care Cancer 1993 Nov; 1: 331–3PubMedCrossRefGoogle Scholar
  111. 111.
    Gottlieb JE, Elmer M, Steiner R. Efficacy of intravenous ICI 200,880, a neutrophil elastase inhibitor, in the treatment of adult respiratory distress syndrome (ARDS) [abstract]. Chest 1994; 106: 67SCrossRefGoogle Scholar
  112. 112.
    Bernard GR, Wheeler AP, Naum CC, et al. A placebo-controlled, randomized trial of IL-10 in acute lung injury (ALI) [abstract]. Chest 1999; 116: 206SCrossRefGoogle Scholar
  113. 113.
    The ARDS Network. Ketoconazole for early treatment of acute lung injury and acute respiratory distress syndrome: a randomized controlled trial. JAMA 2000 Apr; 283: 1995–2002Google Scholar
  114. 114.
    The ARDS Clinical Trial Network. Randomized, placebo-controlled trial of lisofylline for early treatment of acute lung injury and acute respiratory distress syndrome. Crit Care Med 2002 Jan; 30: 1–6Google Scholar
  115. 115.
    Presneill JJ, Harris T, Stewart AG, et al. A randomized phase II trial of granulocyte-macrophage colony-stimulating factor therapy in severe sepsis with respiratory dysfunction. Am J Respir Crit Care Med 2002 Jul 15; 166: 138–43PubMedCrossRefGoogle Scholar
  116. 116.
    Murray JF, Matthay MA, Luce JM, et al. An expanded definition of the adult respiratory distress syndrome [published erratum appears in Am Rev Respir Dis 1989 Apr; 139 (4): 1065.]. Am Rev Respir Dis 1988 Sep; 138: 720–3PubMedGoogle Scholar
  117. 117.
    Vincent JL, Moreno R, Takala J, et al. The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure: on behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. Intensive Care Med 1996 Jul; 22: 707–10PubMedCrossRefGoogle Scholar
  118. 118.
    Knaus WA, Draper EA, Wagner DP, et al. APACHE II: a severity of disease classification system. Crit Care Med 1985 Oct; 13: 818–29PubMedCrossRefGoogle Scholar
  119. 119.
    Knaus WA, Wagner DP, Draper EA, et al. The APACHE III prognostic system: risk prediction of hospital mortality for critically ill hospitalized adults. Chest 1991 Dec; 100: 1619–36PubMedCrossRefGoogle Scholar
  120. 120.
    Marshall JC, Cook DJ, Christou NV, et al. Multiple organ dysfunction score: a reliable descriptor of a complex clinical outcome. Crit Care Med 1995 Oct; 23: 1638–52PubMedCrossRefGoogle Scholar
  121. 121.
    Le Gall JR, Loirat P, Alperovitch A, et al. A simplified acute physiology score for ICU patients. Crit Care Med 1984 Nov; 12: 975–7PubMedCrossRefGoogle Scholar
  122. 122.
    Leo Pharma. HL 10 phase III study [online]. Available from URL: http://www.leopharma.com/w-site/leo/docs.nsf/2addbdd119e92fb08025690a004eb625/797437f3e23f3e95cl256be50024818e?.OpenDocument [Accessed 2004 Apr 20]
  123. 123.
    Guyatt G, Cook D, Devereaux PJ, et al. Therapy. In: Guyatt G, Rennie D, editors. Users’ guides to the medical literature: a manual for evidence-based clinical practice. Chicago: AMA Press, 2002: 55–80Google Scholar
  124. 124.
    Devereaux PJ, Manns BJ, Ghali WA, et al. Physician interpretations and textbook definitions of blinding terminology in randomized controlled trials. JAMA 2001 Apr 18; 285: 2000–3PubMedCrossRefGoogle Scholar
  125. 125.
    Oxman A, Guyatt G, Cook D, et al. Summarizing the evidence. In: Guyatt G, Rennie D, editors. Users’ guides to the medical literature: a manual for evidence-based clinical practice. Chicago: AMA Press, 2002: 155–73Google Scholar
  126. 126.
    Montori V, Guyatt G, Oxman A, et al. Summarizing the evidence: fixed-effects and random-effects models. In: Guyatt G, Rennie D, editors. Users’ guides to the medical literature: a manual for evidence-based clinical practice. Chicago: AMA Press, 2002: 539–46Google Scholar
  127. 127.
    Begg CB. Publication bias. In: Cooper H, Hedges LV, editors. The handbook of research synthesis. New York: Russell Sage Foundation, 1994: 399–409Google Scholar
  128. 128.
    Whitehead J, Stratton I. Group sequential clinical trials with triangular continuation regions. Biometrics 1983 Mar; 39: 227–36PubMedCrossRefGoogle Scholar
  129. 129.
    Marras T, Herridge M, Mehta S. Corticosteroid therapy in acute respiratory distress syndrome. Intensive Care Med 1999 Oct; 25: 1191–3PubMedCrossRefGoogle Scholar
  130. 130.
    ARDS Network. Late steroid rescue study [online]. Available from URL: http://www.ardsnet.org/documents/lasrs6200web.pdf [Accessed 2004 Apr 20]
  131. 131.
    Rubenfeld GD. Epidemiology of acute lung injury. Crit Care Med 2003 Apr 1; 31: S276–84PubMedCrossRefGoogle Scholar
  132. 132.
    Opal SM. Clinical trial design and outcomes in patients with severe sepsis. Shock 2003 Apr; 20: 295–302PubMedCrossRefGoogle Scholar
  133. 133.
    Ferguson ND, Davis A, Chan CK, et al. Development of a modified clinical definition of ARDS using the delphi technique [abstract]. Am J Respir Crit Care Med 2001; 163: A449Google Scholar
  134. 134.
    Villar J, Flores C, Mendez-Alvarez S. Genetic susceptibility to acute lung injury. Crit Care Med 2003; 31(4 Suppl.): S272–5PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2004

Authors and Affiliations

  • Neill Adhikari
    • 1
    Email author
  • Karen E. A. Burns
    • 2
  • Maureen O. Meade
    • 3
  1. 1.Department of Critical Care MedicineSunnybrook and Women’s College Health Sciences CentreTorontoCanada
  2. 2.Department of Critical Care MedicineLondon Health Sciences CentreLondonCanada
  3. 3.Departments of Clinical Epidemiology and Biostatistics and MedicineMcMaster UniversityHamiltonCanada

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