Plasma Thromboxane Concentrations Are Raised in Patients Dying With Septic Shock

Reines, H. David; Cook, James A.; Halushka, Perry V.; Wise, W. C.; Rambo, William M.

doi:10.1016/s0140-6736(82)91027-3

Cited by 139 publications

(27 citation statements)

References 8 publications

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“…Although glucocorticoids have been shown to inhibit TxA2 synthesis in U-937 cells (a monocyte-derived cell line) by a mechanism dependent upon steroid binding (25), steroid receptors have not been reported in platelets, which lack a significant capacity for new protein synthesis. Thus, the lack of a prednisone effect on Tx-M is unsurprising and consistent with similar findings reported in patients in septic shock receiving intravenous steroids (11). PG12 is a major product of endothelial cells in culture (26) and vascular stimulation results in marked augmentation of PGI-M excretion in vivo (27).…”

Section: Discussionsupporting

confidence: 86%

“…Almost all have been performed in animals. These experiments, with rare exception (5), have failed to demonstrate a suppressive effect (6)(7)(8)(9)(10)(11)(12)(13)(14)(15), even in the face of unequivocal inhibition of eicosanoid formation in vitro (10). We have designed a study to evaluate the effects of therapeutic doses of glucocorticoids on the synthesis of eicosanoids in vivo in humans.…”

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confidence: 99%

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Inhibition of eicosanoid biosynthesis by glucocorticoids in humans.

Sebaldt

Sheller

Oates

et al. 1990

Proc. Natl. Acad. Sci. U.S.A.

139

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Therapeutic doses of glucocorticoids are thought to inhibit prostaglandin and leukotriene formation in humans. Several studies in animals, however, have failed to demonstrate modulation of eicosanoid biosynthesis by steroids in vivo. We administered prednisone (60 mg/day) to eight healthy volunteers and measured eicosanoid formation by a variety of cell types in vivo and ex vivo, using sensitive and specific physicochemical assays. We found that the in vivo course of prednisone failed to inhibit the synthesis of thromboxane A2, prostaglandin 12 (prostacyclin), prostaglanin E2, and leukotriene E4 in vivo and of leukotriene B4 ex vivo. Biosynthesis of leukotriene B4, thromboxane B2, and prostaglandins F2 and E2 by macrophage-rich bronchoalveolar lavage cells was strongly suppressed. These findings indicate that therapeutic regimens of glucocorticoids suppress eicosanoid biosynthesis in human macrophages but not in a number of other cell types with steroid receptors, the capacity for eicosanoid formation, and lipocortin-like material. Study Design. In the 7-day study, the eight subjects took 60 mg of prednisone every morning by mouth for 7 days, the equivalent of 8 times the normal total daily production of hydrocortisone. On both of the 2 days immediately before drug treatment and again on both of the final 2 days of this course, heparinized (20 units/ml) whole blood and 24-hr urine collections were obtained. All blood samples were obtained at the same time of day, which at the end of the study was 2 hr after the preceding dose of prednisone. In four of these eight subjects, bronchoalveolar lavage was also performed, initially 1 week before the start and again at the end of the treatment. In the short-term study, the six subjects took 60 mg of prednisone by mouth at 0800 on two consecutive days. Twenty-four-hour urine collections were obtained before and on the first day of drug treatment and heparinized whole blood was obtained 0,1,2,4,8,24, and 30 hr after the first dose.Plasma prednisone and prednisolone concentrations were measured by HPLC (16). The completion of all urine collections obtained in the study was inferred from the close similarity of total creatinine in the four collections obtained from each subject. Prior to storage at -20°C, aliquots (5 ml)were equilibrated with stable-isotope-labeled standards.Whole blood leukocyte stimulation ex vivo was performed as described (17). Heparinized whole blood was divided into aliquots in polypropylene tubes and stimulants were added as follows: freshly opsonized zymosan A (100 and 250 ,ug/ml), the formylated tripeptide fMet-Leu-Phe (1 and 2 ,tM) in the presence of cytochalasin B (5 ttg/ml), anti-human IgE (1 and 2 ,g/ml), or no added stimulant (17). After incubation at 37°C in a shaking water bath for 30 min, the plasma was immediately collected by centrifugation and aliquots were equilibrated with 5 ng of 2H4-labeled LTB4. 6974The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby mark...

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Section: Discussionsupporting

confidence: 86%

mentioning

confidence: 99%

Inhibition of eicosanoid biosynthesis by glucocorticoids in humans.

Sebaldt

Sheller

Oates

et al. 1990

Proc. Natl. Acad. Sci. U.S.A.

139

View full text Add to dashboard Cite

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“…We found that the TXA 2 analogue U46619 promoted O 2 ·Ϫ formation and NADPH oxidase expression in pig PAECs and PAVSMCs. 11 Because hyperactive platelets and increased TXA 2 formation is a hallmark of ARDS, 23 this inhibition may also be beneficial in attenuating oxidative stress and reducing the prohypertensive actions of TXA 2 . 14 One potential drawback of orally administered nitroaspirins, however, is their possible contraindication in sepsis, which etiologically accounts for 40% of ARDS patients.…”

Section: Discussionmentioning

confidence: 99%

“…14 One potential drawback of orally administered nitroaspirins, however, is their possible contraindication in sepsis, which etiologically accounts for 40% of ARDS patients. 23 In contrast to the pulmonary hypertension seen in ARDS, sepsis is associated with systemic hypotension, which is evoked by endotoxin-induced inducible NO synthase expression 24 and as such may be worsened by an NO donor. Indeed, it has been widely advocated that sepsis can be treated with inhibitors of NO synthase.…”

Section: Discussionmentioning

confidence: 99%

Nitroaspirins and Morpholinosydnonimine but Not Aspirin Inhibit the Formation of Superoxide and the Expression of gp91 ^phox Induced by Endotoxin and Cytokines in Pig Pulmonary Artery Vascular Smooth Muscle Cells and Endothelial Cells

et al. 2004

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“…66 Elevated levels of prostanoids such as thromboxane and prostacyclin, which have the potential to alter coronary autoregulation, coronary endothelial function, and intracoronary leukocyte activation, have been demonstrated in septic patients. 67 Early animal studies with cyclooxygenase inhibitors such as indomethacin yielded very promising results. 68,69 Along with other positive results, these led to an important clinical study involving 455 septic patients who were randomized to receive intravenous ibuprofen or placebo.…”

Section: Prostanoidsmentioning

confidence: 99%

Sepsis and the Heart

2007

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Abstract-Sepsis is generally viewed as a disease aggravated by an inappropriate immune response encountered in the afflicted individual. As an important organ system frequently compromised by sepsis and always affected by septic shock, the cardiovascular system and its dysfunction during sepsis have been studied in clinical and basic research for more than 5 decades. Although a number of mediators and pathways have been shown to be associated with myocardial depression in sepsis, the precise cause remains unclear to date. There is currently no evidence supporting global ischemia as an underlying cause of myocardial dysfunction in sepsis; however, in septic patients with coexistent and possibly undiagnosed coronary artery disease, regional myocardial ischemia or infarction secondary to coronary artery disease may certainly occur. A circulating myocardial depressant factor in septic shock has long been proposed, and potential candidates for a myocardial depressant factor include cytokines, prostanoids, and nitric oxide, among others. Endothelial activation and induction of the coagulatory system also contribute to the pathophysiology in sepsis. Prompt and adequate antibiotic therapy accompanied by surgical removal of the infectious focus, if indicated and feasible, is the mainstay and also the only strictly causal line of therapy. In the presence of severe sepsis and septic shock, supportive treatment in addition to causal therapy is mandatory. The purpose of this review is to delineate some characteristics of septic myocardial dysfunction, to assess the most commonly cited and reported underlying mechanisms of cardiac dysfunction in sepsis, and to briefly outline current therapeutic strategies and possible future approaches. Morbidity and mortality are high, resulting in sepsis and septic shock being the 10th most common cause of death in the United States. 5 The incidence of sepsis and sepsis-related deaths appears to be increasing by 1.5% per year. 6 In a recent study, 6 the total national hospital cost invoked by severe sepsis in the United States was estimated at approximately $16.7 billion on the basis of an estimated severe sepsis rate of 751 000 cases per year with 215 000 associated deaths annually. A recent study from Britain documented a 46% in-hospital mortality rate for patients presenting with severe sepsis on admission to the intensive care unit. 7 As an important organ system frequently affected by sepsis and always affected by septic shock, the cardiovascular system and its dysfunction during sepsis have been studied in clinical and basic research for more than 5 decades. In 1951, Waisbren was the first to describe cardiovascular dysfunction due to sepsis. 8 He recognized a hyperdynamic state with full bounding pulses, flushing, fever, oliguria, and hypotension. In addition, he described a second, smaller patient group who presented clammy, pale, and hypotensive with low volume pulses and who appeared more severely ill. With hindsight, the latter group might well have been volume underresuscitated...

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Plasma Thromboxane Concentrations Are Raised in Patients Dying With Septic Shock

Cited by 139 publications

References 8 publications

Inhibition of eicosanoid biosynthesis by glucocorticoids in humans.

Inhibition of eicosanoid biosynthesis by glucocorticoids in humans.

Nitroaspirins and Morpholinosydnonimine but Not Aspirin Inhibit the Formation of Superoxide and the Expression of gp91 ^phox Induced by Endotoxin and Cytokines in Pig Pulmonary Artery Vascular Smooth Muscle Cells and Endothelial Cells

Sepsis and the Heart

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Plasma Thromboxane Concentrations Are Raised in Patients Dying With Septic Shock

Cited by 139 publications

References 8 publications

Inhibition of eicosanoid biosynthesis by glucocorticoids in humans.

Inhibition of eicosanoid biosynthesis by glucocorticoids in humans.

Nitroaspirins and Morpholinosydnonimine but Not Aspirin Inhibit the Formation of Superoxide and the Expression of gp91 phox Induced by Endotoxin and Cytokines in Pig Pulmonary Artery Vascular Smooth Muscle Cells and Endothelial Cells

Sepsis and the Heart

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Product

Resources

About

Nitroaspirins and Morpholinosydnonimine but Not Aspirin Inhibit the Formation of Superoxide and the Expression of gp91 ^phox Induced by Endotoxin and Cytokines in Pig Pulmonary Artery Vascular Smooth Muscle Cells and Endothelial Cells