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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

Abstract Rationale Small, open-label studies suggest that combinations of existing therapies may be effective for pulmonary arterial hypertension (PAH). Objective To evaluate the safety and efficacy of adding inhaled iloprost, a prostacyclin analog, to the endothelin receptor antagonist bosentan in patients with PAH. Methods In a randomized, multicenter, double-blind trial, inhaled iloprost (5 μg) or placebo was added to stable monotherapy with bosentan for 12 wk. Efficacy endpoints included change from baseline in 6-min-walk distance (6-MWD), modified New York Heart Association (NYHA) functional class, hemodynamic parameters, and time to clinical worsening. Measurements and Main Results A total of 67 patients with PAH (55% idiopathic PAH, 45% associated PAH, 94% NYHA class III, and mean baseline 6-MWD of 335 m) were randomized. At Week 12, patients receiving iloprost had a mean increase in 6-MWD of 30 m (p = 0.001); placebo patients had a mean 6-MWD increase of 4 m (p = 0.69), with a placebo-adjusted difference of +26 m (p = 0.051). NYHA status improved by one class in 34% of iloprost versus 6% of placebo patients (p = 0.002). Iloprost delayed the time to clinical worsening (p = 0.0219). Improvements were noted in postinhalation placebo-adjusted change in mean pulmonary artery pressure (−8 mm Hg; p < 0.001) and pulmonary vascular resistance (−254 dyn · s · cm−5; p < 0.001). Combination therapy was well tolerated. Conclusions Within the limitations of a relatively small sample size, results of this study demonstrate that the addition of inhaled iloprost in patients with PAH with reduced exercise capacity on bosentan monotherapy is safe and efficacious.

Introduction There are no treatments directly targeting the pulmonary vasculature in chronic obstructive pulmonary disease (COPD), and further characterization of the underlying endothelial cell (EC) abnormalities could be helpful in drug development. Methods We investigated the influence of exercise and the prostacyclin analog iloprost on extracellular vesicles derived from ECs (eEVs) in 15 moderate–severe COPD patients who were enrolled in a randomized, placebo‐controlled crossover trial of iloprost. Results Active smokers had a profile consistent with inflammatory‐derived EVs, while exacerbation‐prone COPD subjects had a profile consistent with apoptosis‐derived eEVs. There were no significant effects of iloprost on eEV levels. However, there was a significant increase in CD144+ and CD31+/CD144+ EVs 1 h after exercise. Conclusions Endothelial‐derived EV profiles differed based on smoking and exacerbation history. Iloprost did not affect eEV levels, although maximal exercise induced a delayed increase in a subset of eEVs, possibly through shear stress. In this secondary analysis of a placebo‐controlled crossover trial enrolling COPD patients, there was no difference in exercise‐induced changes of endothelial‐derived extracellular vesicles (eEVs) between iloprost and placebo. The eEV profile was different based on smoking and exacerbation history. Compared to baseline values, eEV levels increased 1 h after maximal exercise.

To the Editor: Many alternatives have been proposed for the treatment of frostbite: hemodilution, platelet-aggregation inhibitors, low-molecular-weight heparin, alpha-adrenergic vasodilators, calcium-channel inhibitors, nonsteroidal antiinflammatory agents, prostacyclin analogues, fibrinolytic agents, and hyperbaric oxygen. None have been assessed in prospective randomized trials. Small retrospective studies 1 – 3 suggest the efficacy of thrombolysis or prostacyclin analogues against spasm and thrombosis. Between 1996 and 2008, we randomly assigned 47 patients (44 men and 3 women) with severe frostbite to one of three treatment regimens in an open-label study. Severe frostbite was defined as having at least one digit (finger or toe) with frostbite stage 3 . . .

Inhaled iloprost potentially improves hemodynamics and gas exchange in patients with chronic obstructive pulmonary disease (COPD) and secondary pulmonary hypertension (PH). To evaluate acute effects of aerosolized iloprost in patients with COPD-associated PH. A randomized, double blind, crossover study was conducted in 16 COPD patients with invasively confirmed PH in a single tertiary care center. Each patient received a single dose of 10 µg iloprost (low dose), 20 µg iloprost (high dose) and placebo during distinct study-visits. The primary end-point of the study was exercise capacity as assessed by the six minute walking distance. Both iloprost doses failed to improve six-minute walking distance (p = 0.36). Low dose iloprost (estimated difference of the means -1.0%, p = 0.035) as well as high dose iloprost (-2.2%, p<0.001) significantly impaired oxygenation at rest. Peak oxygen consumption and carbon dioxide production differed significantly over the three study days (p = 0.002 and p = 0.003, accordingly). As compared to placebo, low dose iloprost was associated with reduced peak oxygen consumption (-76 ml/min, p = 0.002), elevated partial pressure of carbon dioxide (0.27 kPa, p = 0.040) and impaired ventilation during exercise (-3.0l/min, p<0.001). Improvement of the exercise capacity after iloprost inhalation in patients with COPD-associated mild to moderate PH is very unlikely. Controlled-Trials.com ISRCTN61661881.

Objectives To investigate the effect of continuous infusion of the potential endothelial cytoprotective agent prostacyclin (Iloprost) 1 ng/kg/min vs. placebo for 72 hours on pulmonary endotheliopathy in mechanically ventilated COVID-19 patients. Trial design A multicenter, randomized (1:1, active: placebo), blinded, parallel group exploratory trial Participants Inclusion criteria are: Adult patients (>18 years); Confirmed COVID-19 infection; Need for mechanical interventions; Endothelial biomarker soluble thrombomodulin >4ng/ml. Exclusion criteria: Withdrawal from active therapy; Pregnancy (non-pregnancy confirmed by patient being postmenopausal (age 60 or above) or having a negative urine- or plasma-hCG); Known hypersensitivity to iloprost or to any of the other ingredients; Previously included in this trial or a prostacyclin trial within 30 days; Consent cannot be obtained; Life-threatening bleeding defined by the treating physician; Known severe heart failure (NYHA class IV); Suspected acute coronary syndrome The study is conducted at five intensive care units in the Capital Region of Denmark at Rigshospitalet, Herlev Hospital, Hvidovre Hospital, Bispebjerg Hospital, Nordsjællands Hospital. Intervention and comparator The patients are randomized to 72-hours continuous infusion of either prostacyclin (Iloprost/Ilomedin) at a dose of 1 ng/kg/min or Placebo (normal saline). Main outcomes Primary endpoint: Days alive without mechanical ventilation in the intensive care units within 28 days Randomisation The randomisation sequence is performed in permuted blocks of variable sizes stratified for trial site using centralised, concealed allocation. The randomisation sequence is generated 1:1 (active/placebo) using the online randomisation software ‘Sealed Envelope’ ( https://www.sealedenvelope.com/ ). Once generated the randomisation sequence is formatted and uploaded into Research Electronic Data Capture system (REDCap) to facilitate centralised, web-based allocation according to local written instruction. Blinding (masking) The following are blinded: all clinicians, patients, investigators, and those assessing the outcomes including the statisticians. Numbers to be randomised (sample size) Forty patients are planned to be randomized to each group, with a total sample size of 80 patients. Trial Status Protocol version 1.4 dated May 25, 2020. Recruitment is ongoing. The recruitment was started June 15, 2020 and the anticipated finish of recruitment is February 28, 2021 with 90 days follow up hereafter. Trial registration Trial registration at clinicaltrialregisters.eu; EudraCT no. 2020-001296-33 on 3 April 2020 and at ClinicalTrials.gov Identifier: NCT04420741 on 9 June 2020 Full protocol The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1 ).In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Objectives Pilot study to compare the effect of inhaled nitric oxide (iNO) and aerosolized iloprost in preventing perioperative pulmonary hypertensive crises (PHTCs). Background Guidelines recommend the use of iNO to treat PHTCs, but treatment with iNO is not an ideal vasodilator. Aerosolized iloprost may be a possible alternative to iNO in this setting. Methods Investigator-initiated, open-label, randomized clinical trial in 15 infants (age range 77–257 days) with left-to-right shunt (11 out of 15 with additional trisomy 21), and pulmonary hypertension (i.e. mean pulmonary artery pressure [PAP] >25 mmHg) after weaning from cardiopulmonary bypass. Patients were randomized to treatment with iNO at 10 ppm or aerosolized iloprost at 0.5 µg/kg (every 2 h). The observation period was 72 h after weaning from cardiopulmonary bypass. The primary endpoint was the occurrence of PHTCs; the secondary endpoints were mean PAP, duration of mechanical ventilation, safety of administration, and in-hospital mortality. Results Seven patients received iNO and eight patients received iloprost. During the observation period, 13 of the 15 patients had at least one major or minor PHTC. There was no difference between the groups with regard to the frequency of PHTCs, mean PAP and duration of mechanical ventilation ( p  > 0.05). Conclusions In this pilot study, aerosolized iloprost had a favorable safety profile. Larger trials are needed to compare its efficacy to iNO for the treatment of perioperative pulmonary hypertension. However, neither treatment alone abolished the occurrence of PHTCs.

Objectives This randomized, controlled trial aimed to investigate whether acute improvement of pulmonary congestion would reduce the severity of Cheyne-Stokes respiration (CSR) in patients with chronic heart failure (CHF). Methods Twenty-one consecutive patients with CHF and CSR (apnea-hypopnea index [AHI] ≥15/h) underwent right heart catheterization with titration of intravenous (IV) glyceryltrinitrate (GTN) to a maximum tolerable dosage and inhalation of iloprost 10 μg/mL after a washout phase. Maximum tolerable dosages of GTN and iloprost were randomly applied during full cardiorespiratory polysomnography within two split-night procedures and compared with IV or inhaled sodium chloride (NaCl) 0.9 %, respectively. Results GTN (6.2 ± 1.5 mg/h) and iloprost significantly lowered \\mean pulmonary artery pressure (20.1 ± 9.0 to 11.6 ± 4.2 mmHg, p  < 0.001 and 16.9 ± 7.9 to 14.2 ± 6.4 mmHg, p  < 0.01, respectively). Pulmonary capillary wedge pressure was only reduced by GTN (14.0 ± 5.6 to 7.2 ± 3.9 mmHg, p  < 0.001), and there was no significant change in the cardiac index. Sleep studies revealed no significant improvement in markers of CSR severity, including AHI, central apnea index, and CSR cycle length following GTN or iloprost treatment. Significant decreases in blood pressure, mean oxygen saturation, and S3 sleep were documented during GTN infusion. Conclusions Acute improvement of pulmonary congestion by GTN had no immediate impact on CSR severity. Future investigations must therefore include longer treatment periods and treatment regimens that have positive, rather than negative, additional effects on peripheral and central chemoreceptors and sleep structure. Trial registration German Clinical Trial Registry-ID:DRKS00000467 ( www.germanctr.de )

The core pathology of coronavirus disease 2019 (COVID-19) is infection of airway cells by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that results in excessive inflammation and respiratory disease, with cytokine storm and acute respiratory distress syndrome implicated in the most severe cases. Thrombotic complications are a major cause of morbidity and mortality in patients with COVID-19. Patients with pre-existing cardiovascular disease and/or traditional cardiovascular risk factors, including obesity, diabetes mellitus, hypertension and advanced age, are at the highest risk of death from COVID-19. In this Review, we summarize new lines of evidence that point to both platelet and endothelial dysfunction as essential components of COVID-19 pathology and describe the mechanisms that might account for the contribution of cardiovascular risk factors to the most severe outcomes in COVID-19. We highlight the distinct contributions of coagulopathy, thrombocytopathy and endotheliopathy to the pathogenesis of COVID-19 and discuss potential therapeutic strategies in the management of patients with COVD-19. Harnessing the expertise of the biomedical and clinical communities is imperative to expand the available therapeutics beyond anticoagulants and to target both thrombocytopathy and endotheliopathy. Only with such collaborative efforts can we better prepare for further waves and for future coronavirus-related pandemics.This Review summarizes the latest evidence indicating that platelet and endothelial dysfunction are essential components of COVID-19 pathology, describes the potential mechanisms underlying the contribution of cardiovascular risk factors to the most severe outcomes in COVID-19, and highlights the roles of coagulopathy, thrombocytopathy and endotheliopathy in COVID-19 pathogenesis.

Raynaud's phenomenon is common but often comes to medical attention only after many years. This review updates the understanding of the pathogenesis, the approach to management, and current approaches to drug therapy. In his 1862 thesis, Maurice Raynaud describes the condition afflicting a 26-year-old female patient: “Under the influence of a very moderate cold . . . she sees her fingers become ex-sanguine, completely insensible, and of a whitish yellow color. This phenomenon happens often without reason, lasts a variable time, and terminates by a period of very painful reaction, during which the circulation is re-established little by little and recurs to the normal state.” 1 The term “Raynaud’s disease” was used to describe these vascular events until Hutchinson, who argued that multiple etiologic factors could be responsible, introduced the concept of “Raynaud’s . . .