Ibuprofen in Sepsis Study
Condition: Acute Respiratory Distress Syndrome; Lung Diseases; Shock, Septic
MeSH terms: Shock, Septic; Lung Diseases; Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn; Acute Lung Injury
Study type: Interventional
Phase: Phase 3

Summary: 
      To determine the effects of ibuprofen on mortality, development and reversal of shock, and
      adult respiratory distress syndrome, and on Lung Parenchymal Injury Score in adult patients
      with serious infection.
    

Detailed description: 
      BACKGROUND:

      The adult respiratory distress syndrome (ARDS) is a multifactorial disorder most commonly
      occurring secondary to sepsis syndrome. Sepsis syndrome occurs in 250,000 to 500,000 patients
      per year with approximately one-third of these developing ARDS and other organ failures.
      Extensive studies utilizing the sheep endotoxin model of ARDS as well as data from human
      pilot studies suggest that cyclooxygenase inhibitors (in particular, ibuprofen) would be
      useful in the prevention and reversal of many of the pathophysiological abnormalities related
      to sepsis. Animal studies where ibuprofen treatment was given prior to endotoxin have shown
      that ibuprofen can improve oxygenation, pulmonary and systematic hemodynamics, airway
      mechanics, and lung lymph flow. Importantly, animal studies have also shown that established
      airways mechanics abnormalities and pulmonary hypertension can be reversed by ibuprofen even
      when given 2.5 hours post endotoxin. Pilot studies of ibuprofen in patients with sepsis
      syndrome showed that temperature and heart rate were significantly reduced and suggested that
      airway mechanics and oxygenation were improved, shock was reversed and that these changes
      were temporally related to prostaglandin levels in urine and plasma.

      The results of a multicenter study of ibuprofen intervention in patients with sepsis
      performed at two medical centers between 1985 and 1987 demonstrated the antipyretic effect of
      ibuprofen with accompanying decrease in heart rate, reduction in peak airway pressure during
      the time of intervention, and evidence from urine assays of reduced in vivo production of
      PGI2 and TxA2. Results suggested that PGI2 production correlated inversely with systemic
      vascular resistance and the TxA2 production correlated directly with pPA and airway
      resistance. Several parameters indicating beneficial effects tended toward improvement during
      ibuprofen intervention.

      The study was conducted at seven North American clinical centers and included a coordinating
      center and a prostaglandin laboratory. Planning and completion of the protocol and manual of
      operation took place for the first six months of the study. Patient accession extended for
      three and a half years. Data analysis was conducted in the last year.

      DESIGN NARRATIVE:

      Randomized, double-blind, placebo-controlled, multicenter. Recruitment at the seven clinical
      sites began in October 1989 and ended in March 1995. A total of 224 patients were randomized
      in a double-blind fashion to ibuprofen given intravenously every six hours for a total of
      eight doses and 231 patients were randomized to placebo. The major endpoint was mortality
      rate at 30 days after randomization. Before the first dose of the study drug, a baseline
      medical history was taken and a physical examination was performed to document the presumed
      cause, site, and time of onset of the sepsis syndrome. Blood was obtained for culture from at
      least two sites. Infection was classified as occurring in the lungs, peritoneum, or urinary
      tract or at another site or an unknown site. Chest radiographs were obtained at entry and
      scored by the chest radiologist to indicate the presence and severity of pulmonary edema.

      Baseline characteristics of the ibuprofen and placebo groups were balanced with respect to a
      variety of measures that correlate with mortality and morbidity. The mean interval that
      elapsed from the time the patient met the entry criteria to the administration of the study
      drug was 10.7 +/- 0.6 hours in the ibuprofen group and 11.3 +/- 0.6 hours in the placebo
      group. The predominant site of infection was the lung. In each group, infections associated
      with positive blood cultures were considered to have been treated with appropriate
      antibiotics in 96 percent of cases. Rates of organ dysfunction (organ failure) were similar
      in the two groups at the time of randomization, except that renal dysfunction was
      significantly more common in the placebo group.

      The method of calculating the Acute Physiology and Chronic Health Evaluation (APACHE II)
      score was modified so that the score represented a point in time -- that is, it was
      calculated from the baseline data rather than from the worst values obtained during the first
      24 hours of care in the intensive care unit. Data obtained at entry and every four hours
      thereafter for the first 44 hours and then at 72, 96, and 120 hours included the patient's
      temperature, mean systemic blood pressure, respiratory rate, heart rate, urinary output (as
      an hourly average), arterial-blood gas measurements and requirements for antipyretic agents.
      Values for mean blood pressure were calculated with the following formula: (0.33 x systolic
      pressure) + (0.67 x diastolic pressure. When a pulmonary artery catheter was present, the
      cardiac output, pulmonary artery pressure, pulmonary wedge pressure, and central venous
      pressure were measured at baseline and 20 hours later. Blood lactate was measured, and the
      delivery and consumption of oxygen calculated, at baseline and 20 hours. Blood samples were
      obtained at baseline and 20, 44, 72, and 120 hours after study entry for the measurement of
      hemoglobin, the total leukocyte count, the platelet count, bilirubin, serum aspartate
      aminotransferase, lactate dehydrogenase, creatinine, blood urea nitrogen, and electrolytes.
      Data were recorded on the patient's requirements for blood transfusion, intensive care, and
      mechanical ventilation.
    

Intervention name(s): ibuprofen
Intervention type(s): Drug
Intervention MeSH terms: Ibuprofen
Allocation: Randomized
Masking: Double
Primary purpose: Treatment