iloprost and Shock--Septic

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

Septic shock remains a significant cause of death in critically ill patients. During septic shock, some patients will retain microcirculatory disorders despite optimal hemodynamic support (i.e., fluid resuscitation, vasopressors, inotropes). Alterations in the microcirculation are a key pathophysiological factor of organ dysfunction and death in septic shock patients. Ilomedin is a prostacyclin analog with vasodilatory effect and anti-thrombotic properties (i.e., inhibition of platelet aggregation) preferentially at the microcirculatory level. We hypothesize that early utilization of intravenous Ilomedin in septic shock patients with clinical persistence of microperfusion disorders would improve the recovery of organ dysfunction.. The I-MICRO trial is a multicenter, prospective, randomized, double-blinded, placebo-controlled study. We plan to recruit 236 adult patients with septic shock and persistent microcirculatory disorders (i.e., skin mottling or increased capillary refill time) despite hemodynamic support. Participants will be randomized to receive a 48-h intravenous infusion of either Ilomedin or placebo starting at the earliest 6 h and later 24 h after septic shock. The primary outcome will be the change (delta) of sequential organ failure assessment (SOFA) score between randomization and day 7. Secondary outcomes will include mean SOFA score during the first 7 days after randomization, mortality at day 28 post-randomization, number of ventilation-free survival days in the 28 days post-randomization, number of renal replacement therapy-free survival days in the 28 days post-randomization, number of vasopressor-free survival days in the 28 days post-randomization, and mottling score at day 1 after randomization.. The trial aims to provide evidence on the efficacy and safety of Ilomedin in patients with septic shock and persistent microcirculatory disorders.. NCT NCT03788837 . Registered on 28 December 2018.

Topics: Clinical Trials, Phase III as Topic; Double-Blind Method; France; Hemodynamics; Humans; Iloprost; Infusions, Intravenous; Microcirculation; Multicenter Studies as Topic; Organ Dysfunction Scores; Prospective Studies; Randomized Controlled Trials as Topic; Shock, Septic; Treatment Outcome; Vasodilator Agents

Part of the pathophysiology in septic shock is a progressive activation of the endothelium and platelets leading to widespread microvascular injury with capillary leakage, microthrombi and consumption coagulopathy. Modulating the inflammatory response of endothelium and thrombocytes might attenuate this vicious cycle and improve outcome.. The CO-ILEPSS trial was a randomised, placebo-controlled, double-blind, pilot trial. Patients admitted to the intensive care unit with septic shock were randomised and allocated in a 2:1 ratio to active treatment with dual therapy of iloprost 1 ng/kg/min and eptifibatide 0.5 μg/kg/min for 48 h or placebo. The primary outcomes were changes in biomarkers reflecting endothelial activation and disruption, platelet consumption and fibrinolysis. We compared groups with mixed models, post hoc Wilcoxon signed-rank test and Mann-Whitney U test.. We included 24 patients of which 18 (12 active, 6 placebo) completed the full 7-day trial period and were included in the per-protocol analyses of the primary outcomes. Direct comparison between groups showed no differences in the primary outcomes. Analyses of within-group delta values revealed that biomarkers of endothelial activation and disruption changed differently between groups with increasing levels of thrombomodulin (p = 0.03) and nucleosomes (p = 0.02) in the placebo group and decreasing levels of sE-Selectin (p = 0.007) and sVEGFR1 (p = 0.005) in the active treatment group. Platelet count decreased the first 48 h in the placebo group (p = 0.049) and increased from baseline to day 7 in the active treatment group (p = 0.023). Levels of fibrin monomers declined in the active treatment group within the first 48 h (p = 0.048) and onwards (p = 0.03). Furthermore, there was a significant reduction in SOFA score from 48 h (p = 0.024) and onwards in the active treatment group. Intention-to-treat analyses of all included patients showed no differences in serious adverse events including bleeding, use of blood products or mortality.. Our results could indicate benefit from the experimental treatment with reduced endothelial injury, reduced platelet consumption and ensuing reduction in fibrinolytic biomarkers along with improved SOFA score. The results of the CO-ILEPSS trial are exploratory and hypothesis generating and warrant further investigation in a large-scale trial.. Clinicaltrials.com, NCT02204852 (July 30, 2014); EudraCT no. 2014-002440-41.

Topics: Adult; Aged; Double-Blind Method; Drug Combinations; Eptifibatide; Female; Humans; Iloprost; Male; Middle Aged; Organ Dysfunction Scores; Severity of Illness Index; Shock, Septic; Statistics, Nonparametric; Treatment Outcome

To evaluate the effect of dopexamine and iloprost on the plasma disappearance rate (PDR) of indocyanine green (ICG) in patients in septic shock in a prospective clinical trial.. In 40 consecutive patients in septic shock, a femoral arterial fiberoptic catheter (COLD system) and a gastrotonometric probe were placed. Patients received either dopexamine infusion (0.5 microgram/kg body weight/min) or iloprost (1 ng/kg body weight/min) for 24 h i.v. PDR, intramucosal pH of stomach wall (pHi), cardiac index (HI) and intrathoracic blood volume (ITBV) were determined before, 1, 6, and 24 h after dopexamine or iloprost infusion and 1 h after end of infusion.. PDR was significantly increased 24 h after starting dopexamine infusion from 12.2 +/- 1.8%/min to 17.8 +/- 2.2%/min (+45.9%) and 1 h after the end of infusion PDR decreased to baseline values. PDR increased to 16.4 +/- 2.1%/min, 1 h after starting iloprost infusion and increased to a maximum value of 18.6 +/- 2.2%/min (+33.8%, p < 0.05) 24 h after start of infusion compared to the baseline (13.9 +/- 1.7%/min). After the end of infusion PDR decreased to baseline values. Baseline values of pHi were in normal ranges in all groups and there was no change during the observation period. Cardiac index and ITBV were stable during the study. Dosage of norepinephrine could be reduced by dopexamine infusion.. Dopexamine and iloprost have a positive effect on the plasma disappearance rate of ICG and therefore have a protective effect on splanchnic perfusion and liver function, respectively.

Topics: Adult; Aged; Algorithms; Blood Volume; Coloring Agents; Dopamine; Female; Hemodynamics; Humans; Hydrogen-Ion Concentration; Iloprost; Indocyanine Green; Infusions, Intravenous; Liver Circulation; Liver Function Tests; Male; Middle Aged; Prospective Studies; Shock, Septic; Splanchnic Circulation; Vasodilator Agents

To evaluate the effects of the stable prostacyclin analogue iloprost on hepato-splanchnic blood flow, oxygen exchange and metabolism in patients with septic shock.. Prospective clinical study.. Intensive care unit in a university clinic.. Eleven patients with septic shock requiring norepinephrine to maintain mean arterial pressure above 70 mmHg.. Iloprost was incrementally infused to increase cardiac index by 15%.. Splanchnic blood flow (Qspl) was measured using the steady-state indocyanine-green infusion technique and endogenous glucose production rate (EGP) using a stable isotope approach. Systemic and splanchnic oxygen consumption (VO2), the hepato-splanchnic uptake rates of the glucose precursors lactate, pyruvate, alanine and glutamine, the hepatic venous redox state and gastric mucosal-arterial PCO2 gradients were determined. After a baseline measurement, iloprost infusion was started. After 90 min all measurements were repeated and a third measurement was obtained after another 90 min following iloprost withdrawal. Qspl (baseline I: 0.82/0.75-1.08 l x min x m2; iloprost: 0.94/0.88-1.29 l x min x m2; baseline II: 0.87/0.74-1.09 l x min x m2) and splanchnic oxygen delivery (baseline I: 122/103-166 ml x min x m2; iloprost: 134/117-203 ml x min x m2; baseline II: 130/98-158 ml x min x m2) significantly increased. While systemic VO2 significantly increased (baseline I: 139/131-142 ml x min x m2; iloprost: 147/136-164 ml x min x m2; baseline II: 143/133-154 ml x min x m2) splanchnic VO2 increased in 9 of 11 patients which, however, did not reach statistical significance. EGP significantly decreased (baseline I: 23/16-26 micromol x kg x min; iloprost: 16/14-21 micromol x kg x min; baseline II: 18/12-20 micromol x kg x min), whereas all other parameters of energy metabolism remained unchanged.. In patients with septic shock an iloprost-induced increase in cardiac index increased splanchnic blood flow and shifted oxygen utilization from the energy requiring de novo glucose production rate to other oxygen-demanding metabolic pathways.

Topics: Adult; Aged; Blood Glucose; Female; Hemodynamics; Humans; Iloprost; Infusions, Intravenous; Liver Circulation; Male; Middle Aged; Oxygen; Prospective Studies; Shock, Septic; Splanchnic Circulation; Statistics, Nonparametric; Vasodilator Agents

To evaluate the effect of the stable prostacyclin analogue iloprost on the plasma disappearance rate of indocyanine green (PDR) in patients with septic shock.. A prospective clinical study in a university hospital intensive care unit.. 20 patients in septic shock. Patients received iloprost infusion (1 ng/kg per minute) for 24 h.. PDR was determined by a femoral arterial fiberoptic catheter before, 1, 6, and 24 h after start and 1 h after end of iloprost infusion. PDR increased significantly 24 h after start of iloprost infusion (baseline: 13.9 +/- 1.7% vs. 18.6 +/- 2.2%/min) and decreased 1 h after end of infusion (13.7 +/- 1.7%/min; p < 0.002). There was no change in pHi, cardiac index, mean arterial pressure, heart rate, central venous pressure, or intrathoracic blood volume index.. Administration of the stable prostacyclin analogue iloprost significantly increases PDR, indicating improvement in liver function.

Topics: Adult; Aged; Coloring Agents; Drug Monitoring; Dye Dilution Technique; Epoprostenol; Female; Hemodynamics; Humans; Iloprost; Indocyanine Green; Infusions, Intravenous; Liver; Liver Function Tests; Male; Metabolic Clearance Rate; Middle Aged; Prospective Studies; Shock, Septic; Vasodilator Agents

Topics: Administration, Intravenous; Humans; Iloprost; Microcirculation; Shock, Septic; Vasodilator Agents

Symmetric peripheral gangrene (SPG) is a symmetrical distal ischemic lesion on at least 2 or more extremities in the absence of proximal arterial obstruction and vasculitis. It is a rare and severe clinical entity. The aim of this study was to describe clinical symptoms, etiological agents and the management of SPG through a series of 4 cases.. We included all cases of SPG hospitalized between 2000 and 2014. The inclusion criterion was the presence of distal ischemic damage at two or more sites in the absence of large vessel obstruction.. Four patients (2 men and 2 women) were included. The mean age was 43.2±12 years. Two patients had a history of splenectomy. All patients had blackening of the tips of the fingers and toes. Three patients presented with septic shock. The etiology was bacteremia involving Streptococcus pneumoniae in two cases and a malignant form of Mediterranean spotted fever (MSF). In addition to specific antibiotics, we used a potent vasodilator (iloprost) in two cases and curative heparin therapy in two cases. The outcome was favorable in 3 cases, with regression of necrotic lesions. One case required the amputation of non-perfused necrotic fingers and toes.. SPG can complicate MSF in some rare cases. Thorough and repeated skin examinations are essential to ensure timely diagnosis and treatment of GPS in order to improve the prognosis.

Topics: Adult; Amputation, Surgical; Anti-Bacterial Agents; Boutonneuse Fever; Female; Fibrinolytic Agents; Fingers; Gangrene; Heparin; Humans; Iloprost; Male; Pneumococcal Infections; Retrospective Studies; Shock, Septic; Toes; 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

Septic shock was induced by intravenous infusion of live Escherichia coli in pigs to investigate the influences on central hemodynamic, coagulation, and fibrinolytic reactions by a thromboxane A2 (TxA2)-receptor blocker (BM 13.177; n = 6) and a prostacyclin analogue (iloprost or ZK 36,374; n = 7). The early pulmonary vasoconstriction following E coli infusion was attenuated, but not abolished, by BM 13.177. Only minor effects were seen after pretreatment with iloprost. Neither drug had any major effect on the coagulation and fibrinolytic activation. These results confirm that TxA2 is an important, but not the only, mediator of early pulmonary vascular response in porcine septicemia and that neither TxA2 nor prostacyclin is of major importance for the hemostatic reactions in this shock model.

Topics: Animals; Blood Pressure; Epoprostenol; Escherichia coli Infections; Female; Hemodynamics; Hemostasis; Iloprost; Male; Platelet Aggregation; Pulmonary Circulation; Receptors, Prostaglandin; Receptors, Thromboxane; Shock, Septic; Sulfonamides; Vascular Resistance

The purpose of this study was to examine the effects of PGI2 and iloprost, a prostacyclin analog, on the sequelae of experimental endotoxic shock. Endotoxemia was produced in rats by IV injection of 20 mg/kg Salmonella enteritidis (LPS). Mean arterial blood pressure fell from 117 +/- 5 mmHg (N = 22) to 92 +/- 5 mmHg and 71 +/- 10 mmHg at 30 and 180 min post-LPS, respectively. In LPS vehicle-treated rats, blood glucose levels fell from 100 +/- 10 mg/dl to 36 +/- 8 mg/dl at 180 min. Plasma glutamate-oxaloacetate transaminase and lactate dehydrogenase (liver fraction) activities were significantly elevated above concentrations in nonshocked animals, increasing to 426 +/- 86 IU/ml and 1,019 +/- 339 IU/ml, respectively. Infusion of PGI2 or iloprost (0.5 micrograms/kg/min) did not alter the blood pressure response to LPS compared to vehicle controls. PGI2 significantly prevented the LPS-induced hypoglycemia while neither treatment significantly reduced the elevations in plasma enzymes nor prevented the lethality of LPS. Thus, the hemodynamic and biochemical indices of shock severity were not significantly improved by either prostacyclin or iloprost. It is suggested that the beneficial effects of PGI2 or prostacyclin analogs observed in other species during endotoxemia does not extend to the rat.

Topics: Animals; Aspartate Aminotransferases; Blood Glucose; Blood Pressure; Epoprostenol; Iloprost; Isoenzymes; L-Lactate Dehydrogenase; Liver; Male; Rats; Salmonella enteritidis; Shock, Septic; Time Factors