THE CLINICAL-EVALUATION OF NEW DRUGS FOR SEPSIS - A PROSPECTIVE-STUDYDESIGN BASED ON SURVIVAL ANALYSIS

Objective.- To develop a survival model and severity assessment method to estimate the 28-day mortality risk for patients with sepsis syndro me entering phase 2 and 3 drug evaluations. Design.- Retrospective ana lysis of intensive care unit admissions with sepsis syndrome by means of log-normal regression to identify risk factors for 28-day mortality . Prospective application of the model to patients with gram-negative infection meeting sepsis syndrome criteria from separate data collecti on (validation group). Patients.- A total of 58 737 intensive care uni t admissions at 107 hospitals in the United States and Western Europe screened to yield 1195 patients meeting entry criteria for the sepsis syndrome study for the original model; 295 hospitalized patients with gram-negative infection meeting criteria for sepsis syndrome for valid ation. Main Outcome Measures.- Survival time and mortality at 28 days after fulfillment of the sepsis syndrome criteria. Results.- Acute phy siologic abnormalities were the most important prognostic factors infl uencing outcome (82% of total chi2). Specific disease resulting in int ensive care unit admission and the time the patient was in the hospita l and intensive care unit before qualification were also independent r isks, as were age and a clinical history of cirrhosis. The model's ove rall classification accuracy was a Somers' Dyx of .52 (rank correlatio n between predicted risk and 28-day mortality) (receiver operating cha racteristic area, 0.76), with equal accuracy (Dyx=.59; receiver operat ing characteristic area, 0.80) in the independent group of patients. C onclusions.- We created an accurate independent estimate for 28-day mo rtality risk for patients with sepsis syndrome (severe sepsis). This e stimate could improve the evaluation of new drugs by investigating whe ther the drug's benefit varies by patient risk and then determining th e amount of benefit for individual patients.