iloprost and Multiple-Organ-Failure

Thrombotic microangiopathy, including the two related syndromes thrombotic thrombocytopenic purpura and hemolytic-uremic syndrome, is a rare and severe multisystem disorder, due to widespread deposition of intravascular microthrombi consisting mainly of platelets, with subsequent consumption thrombocytopenia, microangiopathic hemolytic anemia, renal abnormalities, and neurologic disturbances. The epidemic, verotoxin-induced hemolytic-uremic syndrome, typically associated with prodromal diarrhea, mainly affects young children in small outbreaks. By contrast, idiopathic thrombotic microangiopathy generally affects adults in a sporadic form; it has a more devastating course and a less favourable outcome. Over 90% of the reported cases in the adult, when untreated, have progressed to death within three months of diagnosis. Since the introduction of plasma exchange, a dramatic change in the prognosis of the disease has taken place, although the mortality rate still remains considerable. Indeed, improved survival is the most striking feature of adult thrombotic microangiopathy compared to some decades ago. In the present article we will focus on the evolving concepts able to exert a considerable impact in the management of the adult idiopathic form of thrombotic microangiopathy.

Topics: Adult; Hemolytic-Uremic Syndrome; Humans; Iloprost; Multiple Organ Failure; Plasma Exchange; Platelet Aggregation; Platelet Aggregation Inhibitors; Purpura, Thrombotic Thrombocytopenic; Thrombosis

In Europe 700.000 new cases of sepsis occur annually and more than 100.000 of these patients die due to multiorgan failure (MOF). We have identified shock-induced endotheliopathy (SHINE) to be associated with development of MOF and mortality. Furthermore, in patients with septic shock those with circulating levels of thrombomodulin (TM) above 10 ng/mL have twice the mortality (56% vs 28%) than those with levels below this level. Pilot studies indicate that infusion of iloprost (1 ng/kg/min) is associated with improved endothelial function in patients with septic shock.. This is a multicenter, randomized, blinded, investigator-initiated, adaptive phase 2B trial in up to 384 patients with septic shock-induced endotheliopathy defined by TM > 10 ng/mL who are allocated 1:1 to 72 hours continuous infusion of iloprost 1 ng/kg/min or placebo (equal volume of saline). The primary outcome is the mean daily modified Sequential Organ Failure Assessment (SOFA) score in the ICU up to day 90. Secondary outcomes include 28- and 90-day all-cause mortality, days alive without vasopressor in the ICU within 90 days, days alive without mechanical ventilation in the ICU within 90 days, days alive without renal replacement therapy in the ICU within 90 days, numbers of serious adverse reactions, and the number of serious adverse events within the first 7 days.. This trial tests the safety and efficacy of iloprost vs placebo for 72 hours in patients with septic shock and SHINE. The outcome measures focus on the potential effect of the intervention to mitigate organ failure.. COMBAT-SHINE trial-EudraCT no. 2019-001131-31-Clinicaltrials.gov: NCT04123444-Ethics Committee no. H-19018258.

Topics: Denmark; Endothelium, Vascular; Humans; Iloprost; Multiple Organ Failure; Organ Dysfunction Scores; Research Design; Shock, Septic; Treatment Outcome; Vasodilator Agents

Topics: Angiogenesis Inducing Agents; Child, Preschool; Combined Modality Therapy; Cross Infection; Debridement; Fatal Outcome; Fingers; Gangrene; Humans; Iloprost; Infant; Ischemia; Male; Meningitis, Meningococcal; Multiple Organ Failure; Nitroglycerin; Platelet Aggregation Inhibitors; Shock, Septic; Staphylococcal Infections; Toes; Tuberous Sclerosis; Vasodilator Agents

Prostacyclin levels are increased in septic patients and several animal models of septic shock, and selective inhibition of cyclooxygenase-2 improved cardiovascular dysfunction in rats treated with lipopolysaccharide (LPS). Here, we examine the specific role of prostacyclin and of the receptor for prostacyclin (IP) in the development of LPS-induced circulatory failure. Intravenous injection of LPS (10 mg/kg) into male Sprague-Dawley rats caused a strong increase in plasma prostacyclin levels, which was paralleled by a decrease in blood pressure and an increase in heart rate. Moreover, LPS injection increased the mRNA expression of the IP receptor in the heart, aorta, lung, liver, adrenal glands, and kidneys. Cotreatment with the IP antagonist CAY-10441 (1, 10, 30, and 100 mg/kg) dose-dependently moderated the LPS-induced changes in mean arterial blood pressure, heart rate, cardiac output, and systemic vascular resistance. The development of cardiovascular failure was ameliorated by CAY-10441 in spite of the typical LPS-induced increases in plasma levels of cytokines and NO. In vitro, cytokines dose- and time-dependently induced IP expression in rat vascular smooth muscle cells. Incubation of cells with the stable IP agonist iloprost in the presence of the phosphodiesterase inhibitor 3-isobutyl-1-mehylxanthine resulted in higher cAMP levels in cytokine-treated cells compared with untreated cells. Taken together, our data demonstrate a prominent role of the prostacyclin/IP system in the development of LPS-induced cardiovascular failure.

Topics: Analysis of Variance; Animals; Blotting, Western; Cells, Cultured; Cytokines; Epoprostenol; Iloprost; Lipopolysaccharides; Male; Models, Animal; Multiple Organ Failure; Muscle, Smooth, Vascular; Probability; Prostaglandins F; Prostaglandins I; Random Allocation; Rats; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sensitivity and Specificity; Shock, Septic

Topics: Administration, Inhalation; Adult; Aerosols; Drug Therapy, Combination; Fatal Outcome; Humans; Iloprost; Male; Multiple Organ Failure; Nitric Oxide; Pulmonary Veno-Occlusive Disease; Vasodilator Agents