The Acute Respiratory Distress Syndrome Clincial Network (ARDSNet)

Objectives:

The ARDS Network is a consortium of clinical centers and a coordinating center to design and test novel therapies for the treatment of Acute Lung Injury (ALI) and Acute Respiratory Distress Syndrome (ARDS). The primary objective of the KARMA trial was to investigate the efficacy and safety of Ketoconazole and Respiratory Management in the treatment of ALI and ARDS. The Ketoconazole arm of the study was later stopped due to an inability to show efficacy. Patients continued to be randomized to the respiratory management arms of the study (ARMA), which compared two ventilator strategies: a tidal volume of 6 mL/kg versus 12 mL/kg. The LARMA phase of the study investigated the efficacy of Lisofylline and Respiratory Management.

Background:

Patients suffering from ARDS are extremely ill, require mechanical ventilation and, despite improvements in medical care and technology, had a mortality rate as high as 50 percent. An excessive inflammatory response is characteristic of ALI of which ARDS represents the most severe end of the pathophysiologic spectrum. The inflammatory response includes increased numbers of neutrophils activated to produce cytokines, proteases, and reactive oxygen intermediates. Pulmonary injury may also be enhanced by alveolar and tissue macrophages as a producer of vasoactive substances, neutrophil chemoattractants, and procoagulant substances. Ketoconazole, a synthetic antifungal imidazole, also has anti-inflammatory activities and may inhibit neutrophil recruitment via several different pathways known to be involved in the development of ALI and ARDS. Lisofylline causes a marked decrease in the circulating levels of the major oxidizable species of free fatty acids and also inhibits proinflammatory intracellular signaling. Mechanical ventilation in patients with ALI and ARDS have traditionally used tidal volumes of 10 to 15 ml per kilogram of body weight. These large tidal volumes are often necessary to achieve normal partial pressure of arterial carbon dioxide and pH, but may induce inflammatory responses through disruption of pulmonary epithelium and endothelium. Mechanical ventilation at lower tidal volumes may reduce injurious lung stretch and decrease the inflammatory response.

Subjects:

Patients were recruited from hospitals at the 10 University centers of the ARDS Network and were eligible if: they were in an ICU and required positive pressure ventilation, had acute onset of significantly impaired oxygenation (PaO2 to FIO2 300), bilateral infiltrates consistent with pulmonary edema, no clinical evidence of left atrial hypertension, and were enrolled within 36 hours of developing these criteria. Exclusion criteria included age less than 18, participation in other clinical trials within the previous 30 days, pregnancy, increased intracranial pressure, neurologic conditions that could impair weaning from ventilator support, chronic respiratory disease, sickle cell disease, burns covering more than 30% of body surface area, bone or marrow transplant history, or comorbid irreversible conditions with a six month mortality rate of at least 50 percent. The Ketoconazole and Lisofylline trials were designed as 2 x 2 factorials and included 220 patients in each trial. A total of 860 patients were randomized into the ventilator management trial. Patients enrolled in the Lisofylline or Ketoconozole studies had to be concurrently enrolled in the ventilator management study and were first randomized into a ventilator strategy and then to drug or placebo.

Conclusions:

Ketoconazole was found to be safe but did not reduce mortality, duration of mechanical ventilation, or improve lung function. Lisofylline was also found to be safe and to have no beneficial effect for patients with ALI or ARDS. Ventilation at lower tidal volumes resulted in reduced mortality and an increase in the number of days without ventilator support. (JAMA, 2000; 283:1995-2002; Crit Care Med, 2002; 30: 1-6; N Engl J Med, 2000; 342: 1301-1308).