Ibuprofen in Sepsis Study
Ibuprofen in Sepsis Study
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.
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.
Men and women patients with known or suspected sites of serious infection if core
 temperature was 38.3 degrees Celsius, heart rate 90 in the absence of beta-blockers,
 respiratory rate 20 or minute ventilation 10 liters per minute. In addition, one o