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)

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Increases in extracellular calcium (Ca++) can alter vascular tone, and thus may result in increased blood pressure (Bp) and reduced renal blood flow (RBF). Ca`+ can stimulate prostaglandin E2 (PGE2) and/or prostacyclin (PGI2) release in vitro, which may modulate Ca`+ vascular effects. However, in man, the effect of Ca" on PG release is not known. To study this, 14 volunteers received low-dose (2 mg/kg Ca`+ gluconate) or high-dose (8 mg/ kg) Ca`+ infusions. The low-dose Ca`+ infusion did not alter systemic or renal hemodynamics, but selectively stimulated PGI2, as reflected by the stable metabolite 6-keto-PGFla in urine (159±21-244±30 ng/g creatinine, P < 0.02). The same Caì nfusion given during cyclooxygenase blockade with indomethacin or ibuprofen was not associated with a rise in PGI2 and produced a rise in Bp and fall in RBF. However, sulindac, reported to be a weaker renal PG inhibitor, did not prevent the Ca++-induced PGI2 stimulation (129±33-283±90, P < 0.02), and RBF was maintained despite similar increases in Bp. The high-dose Ca++ infusion produced an increase in mean Bp without a change in cardiac output, and stimulated urinary 6-keto-PGFla to values greater than that produced by the 2-mg/kg Ca++ dose (330±45 vs. 244±30, P < 0.05). In contrast, urinary PGE2 levels did not change. A Ca++ blocker, nifedipine, alone had no effect on Bp or urinary 6-keto-PGFla levels, but completely prevented the Ca++-induced rise in Bp and 6-keto-PGFla excretion (158±30 vs. 182±38, P > 0.2). However, the rise in 6-keto-PGFla was not altered by the a, antagonist prazosin (159±21-258±23, P < 0.02), suggesting that calcium entry and not ao receptor activation mediates Ca`+ pressor and PGI2 stimulatory effects.These data indicate a new vascular regulatory system in which PGI2 modulates the systemic and renal vascular actions of calcium in man. cular smooth muscle can improve many forms of hypertension (1-4). Transcellular calcium flux also functions as the common in vivo pathway for vasoconstriction induced by arginine vasopressin (AVP), angiotensin II, and norepinephrine (5). Studies in man and experimental animals indicate that a rise in extracellular calcium increases renal vascular resistance, reduces renal blood flow (RBF), and impairs renal function (6-8). Although there is evidence suggesting that calcium can directly produce smooth muscle constriction (9), other studies indicate a more complex interaction with the renin-angiotensin system, catecholamines, and prostaglandins (PG) (10-12).It has been suggested that vasodilatory PG, PGE2, and prostacyclin (PGI2) may be protective modulators of systemic and RBF. This is supported by experiments showing decrements in renal function after cyclooxygenase inhibition during states of ischaemia, hypovolemia, and sodium depletion (13-15).Calcium can directly activate membrane phospholipases to release arachidonic acid from membrane phospholipids, which then can be converted into products including PGE2 and/or PG12. This is supported by in vitro data suggesting that the i...