Sepsis syndrome occurs in 250,000 to 500,000 patients per year with approximately 1/3 of these patients developing Adult Respiratory Distress Syndrome (ARDS) and other organ failures. ARDS is a multifactorial disorder, and is the most common organ failure occurring secondary to sepsis syndrome. Extensive studies utilizing the sheep endotoxin model of ARDS as well as data from human pilot studies suggests that cyclooxygenase inhibitors (ibuprofen, in particular) would be useful in the prevention and reversal of many of the pathophysiological abnormalities related to sepsis. Animal studies in which ibuprofen treatment is given prior to endotoxin have shown that ibuprofen can improve the pathologic alterations in oxygenation, pulmonary and systemic hemodynamics, airway mechanics, and lung lymph flow. Importantly, animal studies have also shown that established airway mechanics abnormalities, pulmonary hypertension, and shock can be reversed by ibuprofen even when given several hours after endotoxin is administered, a time frame consistent with the realities of clinical research and medical therapy. Pilot studies of ibuprofen in patients with sepsis syndrome show that temperature, heart rate and lung mechanics are significantly improved, and suggest that shock is reversed. The physiologic abnormalities are temporally related to changes in prostaglandin concentrations in urine and plasma. We propose to conduct a multicenter randomized prospective double-blind trial of ibuprofen in patients with sepsis syndrome to determine the effect on mortality, shock development and reversal, ARDS development and reversal, gas exchange, airway mechanics, and pulmonary and systemic hemodynamics.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL043167-04
Application #
3361686
Study Section
Clinical Trials Review Committee (CLTR)
Project Start
1990-09-30
Project End
1995-07-31
Budget Start
1993-08-01
Budget End
1994-07-31
Support Year
4
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Yan, S B; Helterbrand, J D; Hartman, D L et al. (2001) Low levels of protein C are associated with poor outcome in severe sepsis. Chest 120:915-22
Russell, J A; Singer, J; Bernard, G R et al. (2000) Changing pattern of organ dysfunction in early human sepsis is related to mortality. Crit Care Med 28:3405-11
Conner, B D; Bernard, G R (2000) Acute respiratory distress syndrome. Potential pharmacologic interventions. Clin Chest Med 21:563-87
Arons, M M; Wheeler, A P; Bernard, G R et al. (1999) Effects of ibuprofen on the physiology and survival of hypothermic sepsis. Ibuprofen in Sepsis Study Group. Crit Care Med 27:699-707
Wheeler, A P; Bernard, G R (1999) Treating patients with severe sepsis. N Engl J Med 340:207-14
Carpenter, C T; Price, P V; Christman, B W (1998) Exhaled breath condensate isoprostanes are elevated in patients with acute lung injury or ARDS. Chest 114:1653-9
Bernard, G R; Wheeler, A P; Russell, J A et al. (1997) The effects of ibuprofen on the physiology and survival of patients with sepsis. The Ibuprofen in Sepsis Study Group. N Engl J Med 336:912-8
Carmichael, L C; Dorinsky, P M; Higgins, S B et al. (1996) Diagnosis and therapy of acute respiratory distress syndrome in adults: an international survey. J Crit Care 11:9-18
Weikert, L F; Bernard, G R (1996) Pharmacotherapy of sepsis. Clin Chest Med 17:289-305
Chittock, D R; Russell, J A (1996) Oxygen delivery and consumption during sepsis. Clin Chest Med 17:263-78

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