Multicenter, randomized, controlled trials evaluating mortality in intensive care: Doomed to fail?

Objectives:To determine how many multicenter, randomized controlled trials have been published that assess mortality as a primary outcome in the adult intensive care unit population, and to evaluate their methodologic quality. Data Source:A sensitive search strategy for randomized controlled trials was conducted in the Cochrane Central Register of Controlled Trials and in MedLine using the PubMed interface. Study Selection:All publications of adult, multicenter randomized controlled trials carried out in the intensive care unit, with mortality as a primary outcome, and including >50 patients were selected. Data Extraction:Seventy-two randomized controlled trials were retrieved and were classified according to their effect on mortality: beneficial, detrimental, or neutral. Data Synthesis:Ten of the studies reported a positive impact of the studied intervention on mortality, seven studies reported a detrimental effect of the intervention, and 55 studies showed no effect on mortality. Conclusions:This literature search demonstrates that relatively few of the randomized controlled trials conducted in intensive care units and using mortality as a primary outcome show a beneficial impact of the intervention on the survival of critically ill patients. Methodological limitations of some of the randomized controlled trials may have prevented positive results. Other forms of evidence and end points other than mortality need to be considered when evaluating interventions in critically ill patients.

[1]  D. Altman.  Statistics and ethics in medical research: III How large a sample? , 1980, British medical journal.

[2]  The Veterans.  Effect of high-dose glucocorticoid therapy on mortality in patients with clinical signs of systemic sepsis. , 1987, The New England journal of medicine.

[3]  T. Clemmer,et al.  A controlled clinical trial of high-dose methylprednisolone in the treatment of severe sepsis and septic shock. , 1987, The New England journal of medicine.

[4]  J. Schellekens,et al.  Treatment of gram-negative septic shock with human IgG antibody to Escherichia coli J5: a prospective, double-blind, randomized trial. , 1988, The Journal of infectious diseases.

[5]  R. Bone,et al.  An early test of survival in patients with the adult respiratory distress syndrome. The PaO2/FIo2 ratio and its differential response to conventional therapy. Prostaglandin E1 Study Group. , 1989, Chest.

[6]  A. Ballabio,et al.  Effects of high-dose IgG on survival of surgical patients with sepsis scores of 20 or greater. , 1991, Archives of surgery.

[7]  C. Sprung,et al.  Treatment of gram-negative bacteremia and septic shock with HA-1A human monoclonal antibody against endotoxin. A randomized, double-blind, placebo-controlled trial. The HA-1A Sepsis Study Group. , 1991 .

[8]  A. Dubin,et al.  Gastric intramucosal pH as a therapeutic index of tissue oxygenation in critically ill patients , 1992, The Lancet.

[9]  S. Chevret,et al.  A controlled trial in intensive care units of selective decontamination of the digestive tract with nonabsorbable antibiotics. The French Study Group on Selective Decontamination of the Digestive Tract. , 1992, The New England journal of medicine.

[10]  C. Hinds,et al.  Elevation of systemic oxygen delivery in the treatment of critically ill patients. , 1994, The New England journal of medicine.

[11]  R. F. Johnston,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 , 1994 .

[12]  K. Dickersin,et al.  Systematic Reviews: Identifying relevant studies for systematic reviews , 1994 .

[13]  S. Opal,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. , 1994, JAMA.

[14]  D G Altman,et al.  Assessing the quality of randomization from reports of controlled trials published in obstetrics and gynecology journals. , 1994, JAMA.

[15]  R. J. Hayes,et al.  Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment effects in controlled trials. , 1995, JAMA.

[16]  Craig R. Smith,et al.  Treatment of septic shock with human monoclonal antibody HA-1A: A randomized, double-blind, placebo-controlled trial , 1995 .

[17]  M. Clarke,et al.  Identifying relevant studies for systematic reviews , 1995, BMJ.

[18]  N. MacIntyre,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. , 1995, Critical care medicine.

[19]  G. Koch,et al.  Efficacy and Safety of Monoclonal Antibody to Human Tumor Necrosis Factor α in Patients With Sepsis Syndrome: A Randomized, Controlled, Double-blind, Multicenter Clinical Trial , 1995 .

[20]  S. Nasraway,et al.  Efficacy and safety of monoclonal antibody to human tumor necrosis factor alpha in patients with sepsis syndrome. A randomized, controlled, double-blind, multicenter clinical trial. TNF-alpha MAb Sepsis Study Group. , 1995, JAMA.

[21]  I. Olkin,et al.  Improving the quality of reporting of randomized controlled trials. The CONSORT statement. , 1996, JAMA.

[22]  S. Opal,et al.  Treatment of septic shock with the tumor necrosis factor receptor:Fc fusion protein. The Soluble TNF Receptor Sepsis Study Group. , 1996, The New England journal of medicine.

[23]  A. Anzueto,et al.  Aerosolized Surfactant in Adults with Sepsis-Induced Acute Respiratory Distress Syndrome , 1996 .

[24]  D. Sackett,et al.  Evidence based medicine: what it is and what it isn't , 1996, BMJ.

[25]  J. Carlet,et al.  INTERSEPT: an international, multicenter, placebo-controlled trial of monoclonal antibody to human tumor necrosis factor-alpha in patients with sepsis. International Sepsis Trial Study Group. , 1996, Critical care medicine.

[26]  S. Opal,et al.  Confirmatory interleukin-1 receptor antagonist trial in severe sepsis: a phase III, randomized, double-blind, placebo-controlled, multicenter trial. The Interleukin-1 Receptor Antagonist Sepsis Investigator Group. , 1997, Critical care medicine.

[27]  Treatment of severe systemic inflammatory response syndrome and sepsis with a novel bradykinin antagonist, deltibant (CP-0127). Results of a randomized, double-blind, placebo-controlled trial. CP-0127 SIRS and Sepsis Study Group. , 1997, JAMA.

[28]  M. Schaller,et al.  Confirmatory platelet-activating factor receptor antagonist trial in patients with severe gram-negative bacterial sepsis: a phase III, randomized, double-blind, placebo-controlled, multicenter trial. BN 52021 Sepsis Investigator Group. , 1998, Critical care medicine.

[29]  G. Meduri,et al.  Effect of prolonged methylprednisolone therapy in unresolving acute respiratory distress syndrome: a randomized controlled trial. , 1998, JAMA.

[30]  S. Nasraway,et al.  Double-blind randomised controlled trial of monoclonal antibody to human tumour necrosis factor in treatment of septic shock , 1998, The Lancet.

[31]  F Lemaire,et al.  Tidal volume reduction for prevention of ventilator-induced lung injury in acute respiratory distress syndrome. The Multicenter Trail Group on Tidal Volume reduction in ARDS. , 1998, American journal of respiratory and critical care medicine.

[32]  C. Carvalho,et al.  Effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome. , 1998, The New England journal of medicine.

[33]  Arthur S Slutsky,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. , 1998, The New England journal of medicine.

[34]  S. Kleinman,et al.  A Multicenter, Randomized, Controlled Clinical Trial of Transfusion Requirements in Critical Care , 1999 .

[35]  D. Gens,et al.  Diaspirin Cross-Linked Hemoglobin (DCLHb) in the Treatment of Severe Traumatic Hemorrhagic Shock: A Randomized Controlled Efficacy Trial , 1999 .

[36]  E J Topol,et al.  Cause of death in clinical research: time for a reassessment? , 1999, Journal of the American College of Cardiology.

[37]  J. Vincent.  Which therapeutic interventions in critical care medicine have been shown to reduce mortality in prospective, randomized, clinical trials? A survey of candidates for the Belgian Board Examination in Intensive Care Medicine , 2000, Critical care medicine.

[38]  OLAND,et al.  TREATMENT OF SEPTIC SHOCK WITH THE TUMOR NECROSIS FACTOR RECEPTOR : Fc FUSION PROTEIN C , 2000 .

[39]  F. Gordo,et al.  Prospective randomized trial comparing pressure-controlled ventilation and volume-controlled ventilation in ARDS. For the Spanish Lung Failure Collaborative Group. , 2000, Chest.

[40]  T. Similowski,et al.  Invasive and Noninvasive Strategies for Management of Suspected Ventilator-Associated Pneumonia , 2000, Annals of Internal Medicine.

[41]  F. Gordo,et al.  Prospective randomized trial comparing pressure-controlled ventilation and volume-controlled ventilation in ARDS. For the Spanish Lung Failure Collaborative Group. , 2000, Chest.

[42]  L. U. G. Attinoni,et al.  A TRIAL OF GOAL-ORIENTED HEMODYNAMIC THERAPY IN CRITICALLY ILL PATIENTS , 2000 .

[43]  Rian,et al.  THE EFFECTS OF IBUPROFEN ON THE PHYSIOLOGY AND SURVIVAL OF PATIENTS WITH SEPSIS , 2000 .

[44]  Ketoconazole for early treatment of acute lung injury and acute respiratory distress syndrome: a randomized controlled trial. The ARDS Network. , 2000, JAMA.

[45]  J. A. Kruse,et al.  E5 murine monoclonal antiendotoxin antibody in gram-negative sepsis: a randomized controlled trial. E5 Study Investigators. , 2000, JAMA.

[46]  D. Schoenfeld,et al.  Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. , 2000, The New England journal of medicine.

[47]  J. Takala,et al.  Effect of dopexamine on outcome after major abdominal surgery: A prospective, randomized, controlled multicenter study , 2000, Critical care medicine.

[48]  Ook.,et al.  EVALUATION OF A VENTILATION STRATEGY TO PREVENT BAROTRAUMA IN PATIENTS AT HIGH RISK FOR ACUTE RESPIRATORY DISTRESS SYNDROME , 2000 .

[49]  G. Van den Berghe,et al.  Increased mortality associated with growth hormone treatment in critically ill adults. , 2000, The New England journal of medicine.

[50]  R. Kaplan,et al.  A randomized clinical trial of continuous versus intermittent dialysis for acute renal failure. , 2001, Kidney international.

[51]  J. Vincent,et al.  A multi-centre, double-blind, placebo-controlled study of liposomal prostaglandin E1 (TLC C-53) in patients with acute respiratory distress syndrome , 2001, Intensive Care Medicine.

[52]  S. Opal,et al.  Caring for the critically ill patient. High-dose antithrombin III in severe sepsis: a randomized controlled trial. , 2001, JAMA.

[53]  J. Vincent,et al.  Randomized, placebo-controlled trial of the anti-tumor necrosis factor antibody fragment afelimomab in hyperinflammatory response during severe sepsis: The RAMSES Study , 2001, Critical care medicine.

[54]  Doctors' perceptions of the effects of interventions tested in prospective, randomised, controlled, clinical trials: results of a survey of ICU physicians , 2001, Intensive Care Medicine.

[55]  D. Cook,et al.  On the need for observational studies to design and interpret randomized trials in ICU patients: a case study in stress ulcer prophylaxis , 2001, Intensive Care Medicine.

[56]  ntonio,et al.  EFFECT OF PRONE POSITIONING ON THE SURVIVAL OF PATIENTS WITH ACUTE RESPIRATORY FAILURE , 2001 .

[57]  Jorge A. López,et al.  Early enteral nutrition in critically ill patients with a high-protein diet enriched with arginine, fiber, and antioxidants compared with a standard high-protein diet. The effect on nosocomial infections and outcome. , 2001, JPEN. Journal of parenteral and enteral nutrition.

[58]  S. Opal,et al.  High-Dose Antithrombin III in Severe Sepsis: A Randomized Controlled Trial , 2001 .

[59]  J Ean,et al.  Efficacy and safety of recombinant human activated protein C for severe sepsis. , 2001, The New England journal of medicine.

[60]  P. Gay,et al.  Noninvasive proportional assist ventilation for acute respiratory insufficiency. Comparison with pressure support ventilation. , 2001, American journal of respiratory and critical care medicine.

[61]  T. Butler,et al.  Lenercept (p55 tumor necrosis factor receptor fusion protein) in severe sepsis and early septic shock: A randomized, double-blind, placebo-controlled, multicenter phase III trial with 1,342 patients , 2001, Critical care medicine.

[62]  J. Tijssen,et al.  Effects of early high-volume continuous venovenous hemofiltration on survival and recovery of renal function in intensive care patients with acute renal failure: A prospective, randomized trial , 2002, Critical care medicine.

[63]  Peter Jüni,et al.  Quality of reporting of randomized trials as a measure of methodologic quality. , 2002, JAMA.

[64]  Arthur S Slutsky,et al.  Randomized, placebo-controlled trial of lisofylline for early treatment of acute lung injury and acute respiratory distress syndrome , 2002, Critical care medicine.

[65]  J. Karlawish,et al.  The continuing unethical conduct of underpowered clinical trials. , 2002, JAMA.

[66]  J. Vincent,et al.  Multicenter, double-blind, placebo-controlled study of the use of filgrastim in patients hospitalized with pneumonia and severe sepsis* , 2003, Critical care medicine.

[67]  A. Norrby-Teglund,et al.  Intravenous immunoglobulin G therapy in streptococcal toxic shock syndrome: a European randomized, double-blind, placebo-controlled trial. , 2003, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[68]  Steven B. Johnson,et al.  Multicenter evaluation of a human monoclonal antibody to Entero-bacteriaceae common antigen in patients with Gram-negative sepsis , 2003, Critical care medicine.

[69]  Jill P Pell,et al.  Parachute use to prevent death and major trauma related to gravitational challenge: systematic review of randomised controlled trials. , 2004, The International journal of prosthodontics.

[70]  Michel Wolff,et al.  Comparison of 8 vs 15 days of antibiotic therapy for ventilator-associated pneumonia in adults: a randomized trial. , 2003, JAMA.

[71]  R. Brant,et al.  A randomized, controlled trial of the use of pulmonary-artery catheters in high-risk surgical patients. , 2003, The New England journal of medicine.

[72]  L. Brochard,et al.  Early use of the pulmonary artery catheter and outcomes in patients with shock and acute respiratory distress syndrome: a randomized controlled trial. , 2003, JAMA.

[73]  Stephen F. Lowry,et al.  Efficacy and safety of LY315920Na/S-5920, a selective inhibitor of 14-kDa group IIA secretory phospholipase A2, in patients with suspected sepsis and organ failure , 2003, Critical care medicine.

[74]  C. Sprung,et al.  Efficacy and safety of tifacogin (recombinant tissue factor pathway inhibitor) in severe sepsis: a randomized controlled trial. , 2003, JAMA.

[75]  Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock , 2003, Current infectious disease reports.

[76]  Quoc V. Le,et al.  Effects of systematic prone positioning in hypoxemic acute respiratory failure: a randomized controlled trial. , 2004, JAMA.

[77]  Robert W. Taylor,et al.  Low-dose inhaled nitric oxide in patients with acute lung injury: a randomized controlled trial. , 2004, JAMA.

[78]  Robyn Norton,et al.  A comparison of albumin and saline for fluid resuscitation in the Intensive Care unit , 2005 .

[79]  G. Bernard,et al.  Neutrophil elastase inhibition in acute lung injury: Results of the STRIVE study , 2004, Critical care medicine.

[80]  Steven B. Johnson,et al.  Efficacy and safety of the monoclonal anti-tumor necrosis factor antibody F(ab′)2 fragment afelimomab in patients with severe sepsis and elevated interleukin-6 levels* , 2004, Critical care medicine.

[81]  Margaret M Parker,et al.  Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock , 2004, Critical care medicine.

[82]  J. Kievit,et al.  Effects of transfusion with red cells filtered to remove leucocytes: randomised controlled trial in patients undergoing major surgery , 2004, BMJ : British Medical Journal.

[83]  A. Anzueto,et al.  Noninvasive positive-pressure ventilation for respiratory failure after extubation. , 2004, The New England journal of medicine.

[84]  S. Opal,et al.  Recombinant human platelet-activating factor acetylhydrolase for treatment of severe sepsis: Results of a phase III, multicenter, randomized, double-blind, placebo-controlled, clinical trial* , 2004, Critical care medicine.

[85]  J. Bakker,et al.  Multiple-center, randomized, placebo-controlled, double-blind study of the nitric oxide synthase inhibitor 546C88: Effect on survival in patients with septic shock* , 2004, Critical care medicine.

[86]  R. Brand,et al.  Double-Blind, Randomized Controlled Trial on the Effect of Leukocyte-Depleted Erythrocyte Transfusions in Cardiac Valve Surgery , 2004, Circulation.

[87]  J. Vincent.  Evidence-based medicine in the ICU: important advances and limitations. , 2004, Chest.

[88]  Marek Ancukiewicz,et al.  Higher versus lower positive end-expiratory pressures in patients with the acute respiratory distress syndrome. , 2009, The New England journal of medicine.

[89]  J. Chiche,et al.  High-volume hemofiltration after out-of-hospital cardiac arrest: a randomized study. , 2005, Journal of the American College of Cardiology.

[90]  R. Rossaint,et al.  Drotrecogin alfa (activated) for adults with severe sepsis and a low risk of death. , 2005, The New England journal of medicine.

[91]  A. Dmitrienko,et al.  LY315920NA/S-5920, a selective inhibitor of group IIA secretory phospholipase A2, fails to improve clinical outcome for patients with severe sepsis* , 2005, Critical care medicine.

[92]  M. Singer,et al.  Assessment of the clinical effectiveness of pulmonary artery catheters in management of patients in intensive care ( PAC-Man ) : a randomised controlled trial , 2022 .

[93]  B. Druss.  Evidence based medicine: does it make a difference? , 2005, BMJ : British Medical Journal.

[94]  R. Kacmarek,et al.  A high positive end-expiratory pressure, low tidal volume ventilatory strategy improves outcome in persistent acute respiratory distress syndrome: A randomized, controlled trial* , 2006, Critical care medicine.

[95]  M. Meade,et al.  Drotrecogin alfa (activated): does current evidence support treatment for any patients with severe sepsis? , 2006, Critical care.

[96]  Gordon R Bernard,et al.  Comparison of two fluid-management strategies in acute lung injury. , 2006, The New England journal of medicine.

[97]  W. Hiddemann,et al.  IgMA-enriched immunoglobulin in neutropenic patients with sepsis syndrome and septic shock: A randomized, controlled, multiple-center trial* , 2006, Critical care medicine.

[98]  G. Bernard,et al.  Pulmonary-artery versus central venous catheter to guide treatment of acute lung injury. , 2006, The New England journal of medicine.

[99]  R. Hyzy,et al.  Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome. , 2006, The New England journal of medicine.

[100]  R. Haynes,et al.  Comparison of top-performing search strategies for detecting clinically sound treatment studies and systematic reviews in MEDLINE and EMBASE. , 2006, Journal of the Medical Library Association : JMLA.

[101]  Didier Payen,et al.  Does dopamine administration in shock influence outcome? Results of the Sepsis Occurrence in Acutely Ill Patients (SOAP) Study* , 2006, Critical care medicine.

[102]  Arthur S Slutsky,et al.  Partial liquid ventilation in adult patients with acute respiratory distress syndrome. , 2006, American Journal of Respiratory and Critical Care Medicine.

[103]  Rafael Fernández,et al.  A multicenter trial of prolonged prone ventilation in severe acute respiratory distress syndrome. , 2006, American journal of respiratory and critical care medicine.

[104]  Lung.  Pulmonary-artery versus central venous catheter to guide treatment of acute lung injury. , 2009 .

[105]  Lung.  Efficacy and Safety of Corticosteroids for Persistent Acute Respiratory Distress Syndrome , 2009 .