Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT00000574 |
| Other study ID # |
212 |
| Secondary ID |
R01HL043167 |
| Status |
Completed |
| Phase |
Phase 3
|
| First received |
October 27, 1999 |
| Last updated |
January 28, 2016 |
| Start date |
September 1990 |
| Est. completion date |
July 1995 |
Study information
| Verified date |
January 2016 |
| Source |
Vanderbilt University |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
United States: Federal Government |
| Study type |
Interventional
|
Clinical Trial 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.
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.
