6-ketoprostaglandin-f1-alpha and Multiple-Organ-Failure

This study has shown that multiple organ failure (MOF) is one of the major causes of death in patients with severe burns. Both the plasma and visceral levels of TXB2 and the TXB2/6-keto-PGF1 alpha ratio were significantly increased. The changed plasma levels of TXB2 and the TXB2/6-keto-PGF1 alpha ratio paralleled the deterioration of the general condition in MOF patients. The circulatory platelet aggregation ratios (CPAR) in the MOF patients initially declined then dropped profoundly at 5-7 days postburn, indicating more microaggregate formation. CPK, LDH and GOT had increased markedly by 1 day, were elevated further at 2-3 days, and remained at supranormal levels for the first 7 days postburn. Degeneration, destruction, oedema, haemorrhage and thrombosis were observed in tissues from patients who died due to heart, lung, renal and hepatic failure. Clinically, 13 of the 16 MOF cases developed organ failure and 11 died between 3 and 7 days postburn. These findings confirmed that the increases of TXA2 and the TXA2/PGI2 ratio in plasma and visceral tissues can be an important factor in the genesis and development of postburn MOF.

Topics: 6-Ketoprostaglandin F1 alpha; Adolescent; Adult; Body Surface Area; Burns; Female; Humans; Male; Middle Aged; Multiple Organ Failure; Prospective Studies; Shock; Thromboxane A2

This study investigated the potential benefits of combination therapy using antithrombin (AT) with danaparoid sodium (DA) compared with the use of AT with unfractionated heparin (UFH) in the treatment of sepsis.. Rats infused with lipopolysaccharide were treated with either DA alone, AT alone, AT plus DA, AT plus UFH, or human serum albumin as controls. AT (125 U/kg) was injected into the AT group immediately after lipopolysaccharide infusion. The AT/DA and AT/UFH groups received the same dose of AT in conjunction with either DA (400 U/kg) or UFH (400 U/kg). The status of the mesenteric microcirculation was examined by intra-vital microscopy and the laboratory indices of coagulation, inflammation, and organ dysfunction were measured.. The coagulation markers were improved following the administration of DA or UFH. The decreases in the WBC counts were significantly suppressed in the AT/DA group. The elevation of IL-6 decreased in the AT, DA, and AT/DA groups (all p<0.01) but not in the AT/UFH group. The prostaglandin I2 levels were significantly elevated only in the AT/DA group (p<0.05). The WBC adhesion was significantly suppressed in the DA, AT/UFH, and AT/DA groups (p<0.05), and the RBC velocity was best maintained in the AT/DA group with no associated increase in capillary hemorrhage. The elevation of ALT and BUN significantly improved only in the AT/DA group. ONCLUSION: Organ dysfunction can thus be alleviated by even moderate doses of AT replacement when co-administered with DA.

Topics: 6-Ketoprostaglandin F1 alpha; Alanine Transaminase; Animals; Anticoagulants; Antithrombins; Blood Urea Nitrogen; Chondroitin Sulfates; Dermatan Sulfate; Drug Therapy, Combination; Fibrinolytic Agents; Heparin; Heparitin Sulfate; Interleukin-6; Leukocyte Count; Lipopolysaccharides; Multiple Organ Failure; Platelet Count; Rats; Rats, Wistar

In this study the authors assessed the sequential release of lipid mediators (TXB2, PGE2, 6-keto-PGF1alpha, LTB4, LTC4, PAF), pro-inflammatory cytokines (IL-6, IL-8, TNF-alpha) and anti-inflammatory cytokines (IL-4, IL-10) in 17 patients undergoing coronary artery bypass graft (CABG) with extracorporeal circulation (ECC). Time course of appearance of inflammatory mediators revealed the early and transient increase in lipid mediator plasma concentrations (6-keto-PGF1alpha, LTB4, LTC4, PAF) whereas cytokines (IL-6, IL-8, IL-10) were involved only in late pre- and post-operative periods. No variation of TXB2, PGE2, IL-4 and TNF-alpha levels were found. No correlation was documented between the levels of lipid mediators and pro- or anti-inflammatory cytokines suggesting that lipidic compounds are not implicated in the genesis of cytokines which appear much later involved. Despite the common use of high doses of aprotinin (a non-specific enzyme inhibitor) in hope to abrogate the inflammatory response to cardiopulmonary bypass procedure, this study reports the persistent release of several inflammatory compounds that might be involved in the post-CABG multiple organ failure syndromes.

Topics: 6-Ketoprostaglandin F1 alpha; Anti-Inflammatory Agents; Cardiopulmonary Bypass; Cytokines; Dinoprostone; Extracorporeal Circulation; Humans; Inflammation Mediators; Interleukin-10; Interleukin-4; Interleukin-6; Interleukin-8; Leukotriene B4; Leukotriene C4; Lipid Metabolism; Lipids; Multiple Organ Failure; Platelet Activating Factor; Prospective Studies; Thromboxane B2; Tumor Necrosis Factor-alpha

1. Endotoxaemia is associated with the expression of the inducible isoform of cyclo-oxygenase, cyclo-oxygenase-2 (COX-2), and an overproduction of arachidonic acid (AA) metabolites. The role of the AA metabolites generated by COX-2 in the circulatory failure and multiple organ dysfunction caused by endotoxin is unclear. Dexamethasone prevents the expression of COX-2 and exerts beneficial effects in animal models of shock. 2. Here we compare the effects of two inhibitors of COX-2 activity, namely NS-398 (5 mg kg(-1), i.p., n=7) and SC-58635 (3 mg kg(-1), i.p., n=9) with those of dexamethasone (3 mg kg(-1), i.p., n=9) on the circulatory failure and organ dysfunction caused by lipopolysaccharide (LPS, E. coli, 6 mg kg(-1), i.v., n=11) in the rat. 3. Endotoxaemia for 6 h caused hypotension, acute renal dysfunction, hepatocellular injury, pancreatic injury and an increase in the plasma levels of 6-keto-PGF1alpha (indicator of the induction of COX-2) and nitrite/nitrate (indicator of the induction of iNOS). 4. Pretreatment of rats with dexamethasone attenuated the hypotension, the renal dysfunction, the hepatocellular and pancreatic injury and the induction of COX-2 and iNOS caused by LPS. In contrast, inhibition of COX-2 activity with SC-58635 or NS-398 neither attenuated the circulatory failure nor the multiple organ failure caused by endotoxin. 5. Thus, the prevention of the circulatory failure and the multiple organ injury/dysfunction caused by dexamethasone in the rat is not due to inhibition of the activity of COX-2. Our results suggest that an enhanced formation of eicosanoids by COX-2 does not contribute to the development of organ injury and/or dysfunction in rats with endotoxaemia.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Celecoxib; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dexamethasone; Endotoxemia; Endotoxins; Hypotension; Isoenzymes; Male; Multiple Organ Failure; Nitrates; Nitrites; Nitrobenzenes; Prostaglandin-Endoperoxide Synthases; Pyrazoles; Rats; Sulfonamides

These serial clinical and experimental studies were designed to clarify the pathogenesis of postburn MODS. Both animal and clinical studies were performed. In animal experiments, 46 male cross-bred dogs were cannulated with Swan-Ganz catheters and 39 of them were inflicted with 50% TBSA third degree burns (7 were used as controls). The burned dogs were randomly divided into 4 groups: immediate infusion, delayed infusion, delayed fast infusion and delayed fast infusion combined with ginsenosides. All dogs were kept under constant barbiturate sedation during the whole study period. Hemodynamics, visceral MDA, mitochondrial respiratory control rate (RCR) and ADP/O ratio, ATP, succinic dehydrogenase (SDH), organ water content as well as light and electron microscopy of visceral tissues were determined. In the clinical study, 61 patients with extensive deep burns were chosen, of which 16 sustained MODS. Plasma TXB2/6-keto-PGF1alpha ratio, TNF, SOD, MDA, circulatory platelet aggregate ratio (CPAR), PGE2, interleukin-1, total organ water content and pathological observations of visceral tissues from patients who died of MODS were carried out. Results demonstrated that ischemic-reperfusion damage due to severe shock, sepsis and inhalation injury are three main causes of postburn death. All inflammatory mediators increased markedly in both animals and patients who sustained organ damage or MODS. SDH, RCR, ADP/O and ATP decreased significantly. These findings suggested that ischemic damage and systemic inflammatory response syndrome (SIRS) initiated by mediators or cytokines might be important in the pathogenesis of postburn MODS.

Topics: 6-Ketoprostaglandin F1 alpha; Adenosine Diphosphate; Adenosine Triphosphate; Adult; Animals; Body Water; Burns; Central Nervous System Agents; Dinoprostone; Dogs; Female; Fluid Therapy; Ginsenosides; Hemodynamics; Humans; Hypnotics and Sedatives; Interleukin-1; Male; Malondialdehyde; Mitochondria; Multiple Organ Failure; Oxygen Consumption; Panax; Plants, Medicinal; Platelet Aggregation; Random Allocation; Reperfusion Injury; Saponins; Sepsis; Shock; Succinate Dehydrogenase; Superoxide Dismutase; Syndrome; Systemic Inflammatory Response Syndrome; Thromboxane B2; Tumor Necrosis Factor-alpha

1. We compared the effects of calpain inhibitor I (inhibitor of the proteolysis of I kappa B and, hence, of the activation of nuclear factor kappa B (NF kappa B) and dexamethasone on (i) the circulatory failure, (ii) multiple organ dysfunction and (iii) induction of the inducible isoforms of nitric oxide (NO) synthase (iNOS) and cyclo-oxygenase (COX-2) in anaesthetized rats with endotoxic shock. 2. Injection of lipopolysaccharide (LPS, E. coli, 10 mg kg-1, i.v.) resulted in hypotension and a reduction of the pressor responses elicited by noradrenaline. This circulatory dysfunction was attenuated by pretreatment of LPS-rats with calpain inhibitor I (10 mg kg-1, i.v., 2 h before LPS) or dexamethasone (1 mg kg-1, i.v.). 3. Endotoxaemia also caused rises in the serum levels of (i) urea and creatinine (renal dysfunction), (ii) alanine aminotransferase (ALT), aspartate aminotransferase (AST) (hepatocellular injury), bilirubin and gamma-glutamyl transferase (gamma GT) (liver dysfunction), (iii) lipase (pancreatic injury) and (iv) lactate. Calpain inhibitor I and dexamethasone attenuated the liver injury, the pancreatic injury, the lactic acidosis as well as the hypoglycaemia caused by LPS. Dexamethasone, but not calpain inhibitor I, reduced the renal dysfunction caused by LPS. 4. Endotoxaemia for 6 h resulted in a substantial increase in iNOS and COX-2 protein and activity in lung and liver, which was attenuated in LPS-rats pretreated with calpain inhibitor I or dexamethasone. 5. Thus, calpain inhibitor I and dexamethasone attenuate (i) the circulatory failure, (ii) the multiple organ dysfunction (liver and pancreatic dysfunction/injury, lactic acidosis, hypoglycaemia), as well as (iii) the induction of iNOS and COX-2 protein and activity in rats with endotoxic shock. We propose that prevention of the activation of NF-kappa B in vivo may be useful in the therapy of circulatory shock or of disorders associated with local or systemic inflammation.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Calpain; Cysteine Proteinase Inhibitors; Dexamethasone; DNA-Binding Proteins; Endotoxemia; I-kappa B Proteins; Lipopolysaccharides; Male; Mice; Multiple Organ Failure; Nitric Oxide Synthase; Proto-Oncogene Proteins; Rats; Rats, Wistar; Shock, Septic; Tosylphenylalanyl Chloromethyl Ketone; Tumor Necrosis Factor-alpha

The study deals with an animal model for the problems of surgical intensive care patients. Following repeated applications of E. coli endotoxin WO 111:B4 under standard conditions, specific hemodynamic and biochemical (TNF, TXA2, PGI2, IL-6, PAF) and morphological (endothelium of the lung) alterations were detected. ARDS patterns induced by the sepsis were analyzed by high-frequency measurement of pressure and flow (385 measurements per breathing cycle). The role of the intestine in sepsis was investigated by ion-selective monitoring of surface potassium activity comparing mucosa and serosa. Every injection of endotoxin was followed by a selective increase of the potassium activity revealing relative ischemia induced by the endotoxin. The profile of the potassium levels on the surface correlates both with the cardiac output and with the prostacyclin levels. The continuous narrowing of the difference between mucosa and serosa, potassium during the period of investigation can be regarded as evidence for pathologic change in permeability fostering the septic course.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Critical Care; Epoprostenol; Escherichia coli Infections; Hemodynamics; Interleukin-6; Intestinal Mucosa; Intestines; Ion Channels; Ischemia; Lung; Microscopy, Electron; Multiple Organ Failure; Platelet Activating Factor; Postoperative Complications; Potassium; Pulmonary Gas Exchange; Respiratory Distress Syndrome; Shock, Septic; Swine; Thromboxane A2; Tumor Necrosis Factor-alpha

To define the pathogenesis of hemodynamical and hemorrheological changes as well as multiple organ failure (MOF) during early postburn stage, we determined the levels of thromboxane A2(TXA2) and prostacyclin (PGI2) and some other related variables in 57 patients, of which 14 were complicated by MOF. The results showed that TXA2/PGI2 ratio increased markedly within 3 days postburn, and its dynamic change paralleled well with changes of hemodynamical and hemorrheological parameters as well as myocardial enzyme spectrum. Both plasma and visceral levels of TXA2/PGI2 ratio were significantly higher in MOF than those in non-MOF cases. The altered TXA2/PGI2 ratio coincided with the clinical course of MOF patients. These findings suggested that TXA2/PGI2 imbalance may be one of the important factors of early postburn damage.

Topics: 6-Ketoprostaglandin F1 alpha; Burns; Female; Humans; Male; Multiple Organ Failure; Thromboxane B2

A prospective study was carried out on 57 patients with total burned surface area (TBSA) over 30%. It was found that myocardial damage occurred early postburn, which was one of the major causes of cardiac dysfunction and failure. The postburn respiratory failure (RF) might be classified into three patterns. The etiology of each pattern varied. The imbalance between thromboxane and prostacyclin in plasma and visceral tissues played important roles in the genesis and development of postburn MOF as well as the causes of pathophysiological alterations in the main factors (including inhalation injury, severe shock and systemic infection) which contributed to occurrence of visceral damage and MOF.

Topics: 6-Ketoprostaglandin F1 alpha; Adolescent; Adult; Burns; Burns, Inhalation; Child; Female; Humans; Male; Multiple Organ Failure; Prospective Studies; Shock, Traumatic; Thromboxane B2

Topics: 6-Ketoprostaglandin F1 alpha; Adolescent; Adult; Burns; Dinoprost; Female; Humans; Male; Middle Aged; Multiple Organ Failure; Thromboxane B2

51 burned patients with TBSA over 30% were studied prospectively. MOF developed in 17 of them. Postburn MOF occurred mainly in those with TBSA over 70%. Mortality of MOF was directly proportional to the number of organs involved. The incidence of pulmonary failure was the highest, and the highest mortality was attributed to renal failure. MOF occurring in the early stage was more related to burn shock, and those occurring in the late stage was predisposed mainly by infection. Oxygen free radicals play an important role in the genesis and development of postburn MOF. In this study, it was revealed that antiperoxidation ability declined, active oxygen was increased, and lipid peroxidation became excessive after the burn injury. It was also found that oxygen free radical-mediated effects produced more serious damages in patients with MOF than those without, and also more in those died than the survivors. The hypoxanthine-xanthine oxidase system was a significant source of oxygen radicals after the burn injury. There were also significant changes in plasma TXA2 and PGI2 levels postburn. The marked increase in TXA2/PGI2 ratio indicated imbalance between TXA2 and PGI2, which was correlated well with burn size and closely related to the development of postburn MOF. The excessive production of TXA2 might trigger or accelerate the formation of microaggregates and thromboxane, subsequently leading to visceral damages and failure.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Burns; Female; Humans; Male; Malondialdehyde; Multiple Organ Failure; Shock, Traumatic; Superoxide Dismutase; Thromboxane B2; Xanthine Oxidase

We compared the time course of plasma and pulmonary lymph levels of thromboxane B2 (TxB2) and 6-keto-prostaglandin (PG)F1 alpha during the development of either the hyperdynamic phase of sepsis or of the multiple organ failure syndrome (MOFS) associated with sepsis in 26 chronically instrumented awake sheep with intravascular catheters and a chronic pulmonary lymph fistula. Using a continuous i.v. infusion of Escherichia coli endotoxin administered at a rate of 20 ng.kg-1.min-1 (group E20, n = 9) resulted in hyperdynamic septic shock with more than 75% of animals surviving after 72 h of continuous endotoxin administration. Infusing endotoxin at a higher dosage (40 ng.kg-1.min-1; group E40, n = 9) resulted in the development of respiratory failure and MOFS with death occurring within 55 hr of endotoxemia. Eight similarly instrumented sheep served as controls. Administration of endotoxin produced within 4 hr in both endotoxin groups a significant increase in arterial plasma concentration of TxB2, which was not significantly different between both endotoxin groups. Thereafter, plasma TxB2 concentrations progressively decreased in the E20 group to reach at 36 hr values significantly lower than those measured in control sheep not given endotoxin. In the E40 group, plasma TxB2 concentrations returned to baseline values during the development of a MOFS. The time course of TxB2 concentrations in pulmonary lymph in both endotoxin groups was similar to that measured in each group in plasma. 6-Keto-PGF1 alpha concentrations in arterial plasma and pulmonary lymph were significantly higher than in controls during the first 20 hr following the start of endotoxin infusion in both endotoxin groups and were not different between these groups. Thereafter, plasma and pulmonary lymph 6-keto-PGF1 alpha concentrations progressively returned to baseline values in the E20 group and remained at these levels up to the end of the study period (72 hr). In the E40 group, plasma 6-keto-PGF1 alpha concentrations also decreased to baseline values during the second day of endotoxemia but then significantly increased in sheep that survived more than 36 hr and developed a hypodynamic septic state. During the first 24 hr of endotoxemia, the plasma TxB2/6-keto-PGF1 alpha ratio was similar in controls and in both endotoxin groups. During the second study day, TxB2/6-keto-PGF1 alpha ratio progressively decreased in both endotoxin groups to reach and maintain values significantly lower than tho

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Escherichia coli; Female; Hemodynamics; Kinetics; Lung; Lymph; Male; Multiple Organ Failure; Sheep; Shock, Septic; Thromboxane B2