The effect of intraoperative and 6-h postoperative intravenous administration of low-dose prostacyclin on the endothelium, hemostasis, and hemodynamics in patients undergoing a pancreaticoduodenoctemy: a randomized-controlled pilot study

Johansson, Pär I.; Mortensen, Christian; Nielsen, Tatiana; Tollund, Carsten; Stensballe, Jakob; Hansen, Carsten P.; Frederiksen, Hans Jørgen; Ostrowski, Sisse Rye

doi:10.1097/meg.0000000000000800

Cited by 17 publications

(13 citation statements)

References 32 publications

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“…Intravenous iloprost has been on the market since the 1990s for the treatment of Pulmonary Arterial Hypertension and critical limb ischemia due to its vasodilating and platelet inhibiting effects . The rationale for this trial is that multiorgan failure in sepsis patients is caused by shock‐induced endotheliopathy and that an endothelial cytoprotective effect of iloprost has been identified . The 1 ng/kg/min dose of Iloprost necessary for the endothelial cytoprotective effect is well below the dose necessary for its vasodilatory and platelet inhibiting effects contributing to the safety of administering the intervention in septic shock patients .…”

Section: Discussionmentioning

confidence: 99%

“…26 The rationale for this trial is that multiorgan failure in sepsis patients is caused by shock-induced endotheliopathy and that an endothelial cytoprotective effect of iloprost has been identified. [14][15][16][17][18][19][20][21][22] The 1 ng/kg/min dose of Iloprost necessary for the endothelial cytoprotective effect is well below the dose necessary for its vasodilatory and platelet inhibiting effects contributing to the safety of administering the intervention in septic shock patients. 22 Furthermore, the current trial has an adaptive design where an interims analysis after the first 200 patients will enable a sample size estimation based on the updated 2016 criteria for septic shock.…”

Section: Interventionmentioning

confidence: 99%

“…[14][15][16][17][18][19] We conducted a clinical trial in healthy volunteers showing that low dose (1 ng/kg/min) of the PGI 2 analogue iloprost (Ilomedin ® , Bayer) did not increase hypotensive episodes or bleeding complications but instead appeared to improve endothelial functionality as evaluated by circulating TM (EudraCT no: 2011-006200-12). The effect of iloprost infusion (1 ng/kg/min) was, thereafter, investigated in randomized, double-blind pilot studies in coronary stent (n = 18), 20 major surgery (n = 56) 21 and septic shock patients (n = 18). 22 These trials showed no increases in the incidences of hypotensive episodes or bleeding or in the transfusion requirements of iloprost infusion, but instead significantly improved endothelial function and integrity, measured by endothelial-derived biomarkers including TM.…”

Section: Introductionmentioning

confidence: 99%

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Efficacy and safety of iloprost in patients with septic shock‐induced endotheliopathy—Protocol for the multicenter randomized, placebo‐controlled, blinded, investigator‐initiated trial

Bestle

Clausen

Søe‐Jensen

et al. 2020

Acta Anaesthesiol Scand

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Background 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. Material and Methods 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. Discussion 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. Trial registration COMBAT‐SHINE trial—EudraCT no. 2019‐001131‐31—Clinicaltrials.gov: NCT04123444—Ethics Committee no. H‐19018258.

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Section: Discussionmentioning

confidence: 99%

Section: Interventionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Efficacy and safety of iloprost in patients with septic shock‐induced endotheliopathy—Protocol for the multicenter randomized, placebo‐controlled, blinded, investigator‐initiated trial

Bestle

Clausen

Søe‐Jensen

et al. 2020

Acta Anaesthesiol Scand

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“…However, in a previous study of safety and efficacy of prostacyclin vs placebo in patients undergoing Whipple surgery, post-operative levels of sVE-cadherin increased 1978 ± 461 pg/ml in the placebo group [25]. Based on this, we would be able to detect a difference of 33% in sVE-cadherin increase between groups with 12 patients in the active treatment group vs 6 patients in the placebo group, with a power of 0.8 and an alfa of 0.05.…”

Section: Methodsmentioning

confidence: 99%

Co-administration of iloprost and eptifibatide in septic shock (CO-ILEPSS)—a randomised, controlled, double-blind investigator-initiated trial investigating safety and efficacy

et al. 2019

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Background 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. Method 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. Results 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. Conclusion 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. Trial registration Clinicaltrials.com, NCT02204852 (July 30, 2014); EudraCT no. 2014-002440-41 Electronic supplementary material The online version of this article (10.1186/...

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“…By inhibiting the adhesion and aggregation of platelets and by improving microcirculation in the colon mucosa, iloprost contributes to the better oxygenation of the tissues (7)(8)(9).…”

Section: Introductionmentioning

confidence: 99%

The Effect of Iloprost in the Healing of Colonic Anastomosis in Rats under Chemotherapy with Irinotecan

Arapoglou¹,

Kambaroudis²,

Grivas³

et al. 2017

chr

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RezumatScop: Am investigat posibilele efecte pozitive ale iloprostului în vindecarea anastomozelor colonice, la şobolani sub chimioterapie intraperitoneală cu irinotecan. Metodă: Patruzeci de şobolani masculi Wistar au fost împărţiţi în patru grupuri. În fiecare caz s-a practicat o colectomie parţială segmentară cu anastomoză termino-terminală. Ulterior li s-a administrat intraperitoneal, ser fiziologic (grupul 1), irinotecan (grupul 2), iloprost (grupul 3), irinotecan şi iloprost (grupul 4). Etapele următoare au constat în: autopsie, examinare macroscopică şi măsurarea presiunii de ruptură anastomotică. Un fragment al anastomozei a fost trimis pentru examen histologic şi pentru determinarea nivelurilor de hidroxiprolină. Rezultate: Frecvenţa fistulei anastomotice, cât şi a formării de aderenţe intraperitoneale au fost semnificativ crescute în grupul 2 comparativ cu celelalte grupuri. Presiunea de liză a anastomozei a fost semnificativ mai scăzută în grupul 2, comparativ cu toate celelalte grupuri; de asemenea, acest indicativ a fost semnificativ crescut în grupul 4 comparativ cu grupul 2. Gradul de leucocitoză, numărul de fibroblasti, nivelele de neocollagen şi hidroxiprolină din grupul 4 au fost semnificativ crescute comparativ cu grupul

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The effect of intraoperative and 6-h postoperative intravenous administration of low-dose prostacyclin on the endothelium, hemostasis, and hemodynamics in patients undergoing a pancreaticoduodenoctemy: a randomized-controlled pilot study

Abstract: Intraoperative and postoperative low-dose prostacyclin infusion is safe and associated with reduced endothelial cell damage in patients undergoing a pancreaticoduodenoctemy compared with those receiving placebo.

Cited by 17 publications

References 32 publications

Efficacy and safety of iloprost in patients with septic shock‐induced endotheliopathy—Protocol for the multicenter randomized, placebo‐controlled, blinded, investigator‐initiated trial

Efficacy and safety of iloprost in patients with septic shock‐induced endotheliopathy—Protocol for the multicenter randomized, placebo‐controlled, blinded, investigator‐initiated trial

Co-administration of iloprost and eptifibatide in septic shock (CO-ILEPSS)—a randomised, controlled, double-blind investigator-initiated trial investigating safety and efficacy

The Effect of Iloprost in the Healing of Colonic Anastomosis in Rats under Chemotherapy with Irinotecan

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