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).
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Study Website |
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Study Documentation |
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Data Distribution Agreement |
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