Prostacyclin and thromboxane A2 formation is increased in human sepsis syndrome. Effects of cyclooxygenase inhibition.
Arachidonic acid metabolites, especially thromboxane-A2 and prostacyclin, have been shown to be increased in experimental models of sepsis and the adult respiratory distress syndrome (ARDS) and play a major pathophysiologic role. This study was designed to determine if these metabolites are increased in human sepsis syndrome and if inhibition of fatty acid cyclooxygenase affects their formation and their pathophysiologic sequelae. We conducted a double-blind, placebo-controlled trial of ibuprofen (800 mg given rectally every 4 h for three doses) in 30 patients with sepsis syndrome defined by abnormal vital signs, the appearance of serious infection, and at least one major organ failure. Urinary concentrations of the metabolite of thromboxane-A2, 2,3-dinor-TxB2, and prostacyclin, 2,3-dinor-6-keto-prostaglandin F2 alpha, were elevated 10 to 20 times normal and declined to four to five times normal by 12 h after entry in the ibuprofen-treated group and remained elevated in the placebo-treated patients. The urinary concentration of TxB2 and 6-keto-prostaglandin F1 alpha, which reflect renal production of TxA2 and prostacyclin, respectively, were also increased approximately 10-fold over normal and were subsequently decreased by ibuprofen. Coincident with the reduction in metabolite levels, the ibuprofen-treated group, but not the placebo-treated group, experienced a significant decline in temperature, heart rate, and peak airway pressure, and a trend towards more rapid reversal of shock (p = 0.12).(ABSTRACT TRUNCATED AT 250 WORDS)
Bernard
G R
GR
Department of Medicine, Vanderbilt School of Medicine, Nashville, Tennessee 37232.
Reines
H D
HD
Halushka
P V
PV
Higgins
S B
SB
Metz
C A
CA
Swindell
B B
BB
Wright
P E
PE
Watts
F L
FL
Vrbanac
J J
JJ
D016861:Cyclooxygenase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D004311:Double-Blind Method; D011464:Epoprostenol / Q000032:analysis / Q000096:biosynthesis*; D006801:Humans; D007052:Ibuprofen / Q000009:adverse effects / Q000627:therapeutic use; D009102:Multiple Organ Failure / Q000188:drug therapy / Q000378:metabolism; D018805:Sepsis / Q000188:drug therapy / Q000378:metabolism*; D013577:Syndrome; D013928:Thromboxane A2 / Q000032:analysis / Q000096:biosynthesis*; D013997:Time Factors
D016861:Cyclooxygenase Inhibitors; D013928:Thromboxane A2; D011464:Epoprostenol; D007052:Ibuprofen