Iloprost Infusion Research Articles

Response to Rituximab after Failure of Cyclophosphamide in the Induction Treatment in a Patient with cANCA-associated Vasculitis and Pachymeningitis: a Case Report

A 36-year-old male patient who originally presented with recurrent inflammations in the mastoid, otitis media and peripheral facial paralysis was diagnosed with sterile pachymeningitis, associated with high titres of antineutrophil cytoplasmic antibodies (cANCA) directed against proteinase 3 (PR3). Induction therapy with oral prednisolone 1 mg/kg body weight and cyclophosphamide (CYC) 750 mg/m 2 i.v. every 4 weeks was initiated. Due to side effects, increasing arthralgias and progressive meningitis after 5 doses of CYC, treatment was changed to rituximab (RTX), one cycle comprising two administrations of 1000 mg RTX i.v. two weeks apart, repeated every 6 months. After the very first cycle of RTX, we confirmed subjective improvement of the patient’s fitness as well as radiologic response. Methotrexate (MTX) was added to ease arthralgias. Painful bleeding ulcerations on finger tips were successfully treated with 22 iloprost infusions. Up to date, we have administered 7 cycles of RTX and achieved complete remission of the cANCA-associated vasculitis. After the induction therapy, maintenance treatment with MTX or rituximab will be performed for at least 18–24 months.We can demonstrate a complete remission with the use of RTX in a patient with cANCA-associated vasculitis and sterile pachymeningitis who failed to respond to the induction treatment with CYC. RTX has been well tolerated.

P033 Scleroderma-like fibrotic disorder associated with a gastro-intestinal stromal tumour which responded only to imatinib

Abstract Background/Aims Gastro-intestinal stromal tumour (GIST) is recognised as the most prevalent mesenchymal tumour of the gastro-intestinal (GI) tract. The vast majority of GIST display activating mutations in receptor tyrosine kinases, such as platelet-derived growth factor receptor alpha (PDGFRA) and c-kit. This characteristic has lead to the development and approval of targeted therapies such as Imatinib for metastatic GIST. Scleroderma is an idiopathic fibrotic syndrome which involves excess collagen deposition in multiple tissues and organs. There is emerging evidence that dysfunctional fibroblasts are central to the underlying pathogenesis of this disease. An increasing awareness of the complex interplay of these fibroblasts with other cells and inflammatory mediators, such as platelet-derived growth factor (PDGF), is being recognised. This novel case serves to further develop our understanding of these pathological interactions, and to highlight a prospective role for Imatinib in disrupting them. Methods We present a case report below. Results A 54-year-old Caucasian male was referred to our rheumatology clinic due to worsening Raynaud's syndrome, arthralgia, and dry cough. He subsequently developed weight loss, pyrosis and skin thickening. This clinical picture was suggestive of a new diagnosis of systemic sclerosis. However, fibrotic skin changes did not extend to the distal finger, and anti-nuclear antibody (ANA) was negative. Symptoms were also refractory to various vasodilator and immunosuppressive therapies, including nifedipine, repeated iloprost infusions, azathioprine, mycophenolic acid, prednisolone, and sildenafil. Computed tomography (CT) imaging revealed interstitial pulmonary fibrosis and a mass within the gastric fundus. Histopathologic features and immunological staining of this mass were consistent with a GIST. Resection of the tumour did not improve fibrotic symptoms. Surveillance imaging one-year later was highly concerning for metastatic recurrence, which was later confirmed with tissue biopsy. He was subsequently initiated on Imatinib therapy, which led to a rapid improvement in fibrotic changes within weeks. Conclusion While there have been previous descriptions of para-neoplastic fibrotic syndromes, this is the first reported case of a scleroderma-mimicking disorder associated with GIST. It hints at an important potential overlap in the pathogenesis of these disease processes, and a potential role for tyrosine-kinase inhibitors in the treatment of scleroderma-like fibrotic disorders. Disclosure Z.A. Butt: None. W. Ng: None. D. Howard: None. K. Osman: None.

Evaluation of Clinical Outcomes After Revascularization in Patients With Chronic Limb-Threatening Ischemia: Results From a Prospective National Cohort Study (RIVALUTANDO)

A prospective, multicenter, cohort study from Italy from December 2016 to December 2018. For 287 patients with chronic limb-threatening ischemia (CLTI) who underwent open, endovascular, or hybrid lower extremity revascularization, the 30-day major adverse cardiovascular and major adverse limb events (MALE) rates were 3% and 2%, respectively. At 1 year, the overall survival, amputation-free survival, freedom from MALE, and primary patency rate was 89%, 87%, 63%, and 71%, respectively. Smoking, renal failure, Rutherford class ≥5, and below-the-knee arterial disease were significant predictors of amputation after multivariate analysis. Iloprost infusion was a significant protective factor against MALE, and cilostazol was a significant protective factor against restenosis. Medical treatment, including statins, cilostazol, and iloprost, were associated with improved 1-year freedom from restenosis and amputation.

Efficacy and safety of iloprost in trauma patients with haemorrhagic shock-induced endotheliopathy-Protocol for the multicentre randomized, placebo-controlled, blinded, investigator-initiated shine-trauma trial.

BackgroundTraumatic injury accounts for 800 000 deaths in the European Union annually. The main causes of deaths in trauma patients are exsanguination and multiple organ failure (MOF). We have studied >1000 trauma patients and identified shock‐induced endotheliopathy (SHINE), the pathophysiological mechanism responsible for MOF and high mortality. Pilot studies indicate that low‐dose iloprost (1 ng/kg/min) improves endothelial functionality in critically ill patients suggesting this intervention may improve patient outcome in traumatic SHINE.Material and MethodsThis is a multicentre, randomized, blinded clinical investigator‐initiated phase 2B trial in trauma patients with haemorrhagic shock‐induced endotheliopathy. Patients are randomized 1:1 to 72 hours infusion of iloprost 1 ng/kg/min or Placebo (equal volume of saline). A total of 220 trauma patients will be included. The primary endpoint is the number of intensive care unit (ICU)‐free days, within 28 days of admission. Secondary endpoints include 28‐ and 90‐day all‐cause mortality, hospital length of stay, vasopressor‐free days in the intensive care unit (ICU) within 28 days, ventilator‐free days in the ICU within 28 days, renal replacement‐free days in the ICU within 28 days, number of serious adverse reactions and serious adverse events within the first 4 days of admission.DiscussionThis trial will test the safety and efficacy of administration of iloprost vs placebo for 72 hours in trauma patients with haemorrhagic shock‐induced endotheliopathy. Trial endpoints focus on the potential effect of iloprost to reduce the need for ICU stay secondary to mitigation of organ failure.Trial registrationSHINE‐TRAUMA trial—EudraCT no. 2019‐000936‐24—Clinicaltrials.gov: NCT03903939 Ethics Committee no. H‐19014482.

Critical limb ischemia patients clinically improving with medical treatment have lower neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios.

Inflammation is a component in the pathogenesis of critical limb ischemia. We aimed to assess how inflammation affects response to treatment in patients treated for critical limb ischemia using neutrophil-to-lymphocyte (NLR) and platelet-to-lymphocytes ratios (PLR) as markers of inflammation. Patients in a single tertiary cardiovascular center with critical limb ischemia unsuitable for surgical or interventional revascularization were retrospectively identified. Data were collected on medical history for risk factors, previous surgical or endovascular revascularization, and outcome. A standard regimen of low molecular weight heparin, aspirin, statins, iloprost infusions, and a standard pain medication protocol were applied to each patient per hospital protocol. Patients with improvement in ischemic pain and healed ulcers made up the responders group and cases with no worsening pain or ulcer size or progression to minor or major amputations made up the non-responders group. Responders and Non-responders were compared for risk factors including pretreatment NLR and PLR. 268 included patients who were not candidates for surgical or endovascular revascularization were identified. Responders had significantly lower pretreatment NLR (4.48 vs 8.47, p < 0.001) and PLR (162.19 vs 225.43, p = 0.001) values. After controlling for associated risk factors NLR ≥ 4.63 (p < 0.001) and PLR ≥ 151.24 (p = 0.016) were independently associated with no response to treatment. Neutrophil-to-lymphocyte ratio and platelet-to-lymphocytes ratio are markers of inflammation that are reduced in patients improving with medical treatment suggesting a decreased state of inflammation before treatment in responding patients.

Evaluation of Clinical Outcomes After Revascularization in Patients With Chronic Limb-Threatening Ischemia: Results From a Prospective National Cohort Study (RIVALUTANDO).

We evaluated the outcomes of revascularization in patients with chronic limb-threatening ischemia (CLTI) treated in real-world settings. This is a prospective multicenter cohort study with 12-month follow-up enrolling patients (n = 287) with CLTI undergoing open, endovascular, or hybrid lower extremity revascularization. The primary end point was amputation-free survival (AFS) at 12 months. Cox proportional analysis was used to determine independent predictors of amputation and restenosis. At 30 days, major adverse cardiovascular and major adverse limb events (MALE) rates were 3.1% and 2.1%, respectively. At 1 year, the overall survival rate was 88.8%, the AFS was 86.6%, and the primary patency was 70.5%. Freedom from MALE was 62.5%. After multivariate analysis, smoking (hazard ratio [HR] = 2.2, P = 0.04), renal failure (HR = 2.3, P = 0.03), Rutherford class (≥5) (HR = 3.2, P = 0.01), and below-the-knee disease (HR = 2.0, P = 0.05) were significant predictors of amputation; iloprost infusion (>10 vials) (HR = 0.64, P = 0.05) was a significant protective factor. Cilostazol administration (HR = 0.77, P = 0.05) was a significant protective factor for restenosis. Results from this prospective multicenter registry offer a consistent overview of clinical outcomes of CLTI patients at 1 year when adequately revascularized. Medical treatment, including statins, cilostazol and iloprost, were associated with improved 1-year freedom from restenosis and amputation.

Periferik Vasküler Hastalığın Tedavisinde İloprost’tun Nitrik Oksit, Asimetrik Dimetilarjinin ve Serotonin’e Etkisi

Aim: In this study, it is aimed to investigate the efficacy of iloprost use in peripheral artery disease patients on the parameters involved in endothelial functions such as circulating acetyl dimethyl arginine (ADMA), serotonin and nitric oxide (NO).&#x0D; Patients and Methods: 30 patients (19 male, 11 female, age interval 60.7 ± 13.7) who were followed-up with the diagnosis of Fontaine III-IV disease and decided to receive a medical treatment were included in the study. Iloprost infusion was initiated as a 16-hour intravenous infusion at the dose of 0.5-1.5 ng / kg / min from the forearm veins and was given for 7 days. Blood was taken for ADMA, Serotonin and NO results before and after the treatment (8th day). Total nitrite (nitrite + nitrate) concentration was measured by the modified cadmium reduction method, ADMA and serotonin levels were measured by High Performance Liquid Chromotography (HPLC) method.&#x0D; Results: ADMA value before and after the iloprost treatment was decreased after the treatment and while this was statistically significant (p=0.001), the changes in serotonin (p=0.82) and NO (P= 0.16) values were found statistically insignificant. &#x0D; Conclisions: Peripheral arterial disease may be a parameter that can be taken into account in the evaluation of treatment for peripheral arterial disease and ADMA, which is considered to be an endothelial dysfunction indicator after iloprost treatment.

Effectiveness of Iloprost in the Treatment of Bone Marrow Edema.

Background and objectiveBone marrow edema (BME) is a rare condition caused by insufficient osseous blood supply and may result in severe pain that has adverse effects on patients’ life. To date, various conservative treatments have been recommended for the treatment of BME, including analgesics, immobilization of the affected extremity, and iloprost infusion. The aim of this retrospective study was to investigate the effectiveness of parenteral iloprost therapy in the treatment of BME detected in different skeletal locations.Materials and methodsThis retrospective study included 23 patients (17 men and six women) with BME who were classified as stage I-III according to the Association Research Circulation Osseous (ARCO) classification. BME was localized to the proximal femur in 13 (56.5%), the distal femur in four (17.4%), tarsal bone in four (17.4%), and tibial plateau in two (8.7%) patients. The mean age of the patients was 46.7 years and all the patients were evaluated with the Visual Analog scale (VAS), Functional Mobility Scale (FMS), and MRI.ResultsA significant improvement was observed in the post-treatment VAS and FMS scores of all patients compared to their pre-treatment scores. Moreover, the edema regressed completely in 60.9% of the patients at three months of MRI control. No serious side effects were observed during the treatment in any of the patients. However, transient side effects including headache, arrhythmia, and flushing were observed in five patients.ConclusionThe present study indicated that iloprost therapy is an effective and safe option in the treatment of BME patients, particularly in the reduction of severe pain that has adverse effects on patients’ social life, regardless of ARCO staging. Moreover, this therapy could be particularly useful in reducing pain, improving functional recovery, and achieving complete regression of the edema on MRI in ARCO stage I-II patients.

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

BackgroundIn 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 MethodsThis 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.DiscussionThis 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 registrationCOMBAT‐SHINE trial—EudraCT no. 2019‐001131‐31—Clinicaltrials.gov: NCT04123444—Ethics Committee no. H‐19018258.

Effects of iloprost on experimental ischemia and reperfusion injury in rat ovary

ABSTRACTWe investigated the protective effect of iloprost against ischemia/reperfusion (I/R) injury in rat ovary. We used 32 female Sprague-Dawley rats randomly allocated to four experimental groups: sham, ischemia, I/R and I/R + iloprost. Ovarian torsion was established in all rats except the sham group. The torsion group was exposed to ischemia for 3 h. The detorsion group was exposed to 3 h ischemia applied + 3 h reperfusion. The detorsion + iloprost group was exposed to ischemia for 3 h + reperfusion for 3 h + intravenous (IV) iloprost infusion for 60 min starting at the beginning of reperfusion. Ovaries were removed and prepared for histopathological evaluation. Reduced glutathione (GSH) and malondialdehyde (MDA) were measured in the blood. The total histopathological injury score and MDA level of the ischemia group were significantly higher than for the sham group. Ovarian injury score and MDA level following I/R increased compared to the ischemia group. Iloprost administration reduced the total injury score and MDA level. The GSH level was higher in the I/R + iloprost group than in the I/R group. We concluded that IV iloprost administration reduces I/R injury in rat ovarian tissue.

Low dose Iloprost effect on platelet aggregation in comatose out-of-hospital cardiac arrest patients: A predefined sub-study of the ENDO-RCA randomized -phase 2- trial

PurposeThis is a predefined sub-study of the Endothelial Dysfunction in Resuscitated Cardiac Arrest (ENDO-RCA) trial. We aim to investigate Iloprost, a prostacyclin analogue, safety by evaluating change in whole blood platelet aggregometry (Multiplate) in out of hospital cardiac arrest (OHCA) patients from baseline to 96-h post randomization. MethodsA randomized, placebo controlled double-blinded trial in 46 OHCA patients. Patients were allocated 1:2 to 48 h Iloprost infusion, (1 ng/kg/min) or placebo (saline infusion). Platelet aggregation was determined by platelet aggregation tests ASPI-test (arachidonic acid); TRAP-test (thrombin-receptor activating peptide (TRAP)-6; RISTO test (Ristocetin); ADP test (adenosin diphosphat). ResultsThere was no significant difference between the iloprost and placebo groups according to ASPI, TRAP, RISTO and ADP platelet aggregation assays. Further, no significant differences regarding risk of bleeding were found between groups (Risk of bleeding: ASPI <40 U; TRAP <92 U; RISTO <35 U; ADP <50 U). ConclusionsIn conclusion, the iloprost infusion did not influence platelet aggregation as evaluated by the ASPI, TRAP, RISTO and ADP assays. There was no increased risk of bleeding or transfusion therapy. A decline in platelet aggregation was observed for the ASPI and ADP assays during the initial 96 h after OHCA.Trial Registration: Trial registration at clinicaltrials.gov (identifier NCT02685618) on 18-02-2016.

“Endothelial Dysfunction in Resuscitated Cardiac Arrest (ENDO-RCA): Safety and efficacy of low-dose Iloprost, a prostacyclin analogue, in addition to standard therapy, as compared to standard therapy alone, in post-cardiac-arrest-syndrome patients.”

ObjectiveAn increasingly recognized prognostic factor for out-of-hospital-cardiac-arrest (OHCA) patients is the ischemia-reperfusion injury after restored blood circulation. Endothelial injury is common in patients resuscitated from cardiac arrest and is associated with poor outcome. This study was designed to investigate if iloprost infusion, a prostacyclin analogue, reduces endothelial damage in OHCA patients. Methods50 patients were randomized in a placebo controlled double-blinded trial and allocated 1:2 to 48-hours iloprost infusion, (1 ng/kg/min) or placebo (saline infusion). Endothelial biomarkers (soluble thrombomodulin (sTM), sE-selectin, syndecan-1, soluble vascular endothelial growth factor (sVEGF), vascular endothelial cadherine (VEcad), nucleosomes) and sympathoadrenal activation (epinephrine/norepinephrine) from baseline to 48 and 96-hours were evaluated. ResultsIloprost infusion did not influence endothelial biomarkers by the 48-hour endpoint. A rebound effect was observed with higher biomarker plasma values in the iloprost group (sTM p=0.02; Syndecan p=0.004; nucleosomes p<0.001; VEcad p<0.03) after 96-hours. There was a significant difference in 180-day mortality in favor of placebo. There was no difference regarding total adverse events between groups (p=0.73). Two patients were withdrawn in the iloprost group due to hypotension. ConclusionsThe administration of low-dose iloprost (1ng/kg/min) to OHCA patients did not significantly influence endothelial biomarkers as measured by the 48- hour endpoint. A rebound effect was however observed in the 96-hour statistical model, with increasing endothelial biomarker levels after cessation of the iloprost-infusion.

44. Buerger’s disease with severe eosinophilia and acute critical ischemia

IntroductionBuerger’s disease usually presents with normal blood tests. We present a case with significant eosinophilia, a phenomenon rarely reported. Eosinophilia with acute onset Raynaud’s and critical ischemia can be atypical early manifestation of Buerger’s disease (thromboangiitis obliterans).Case descriptionA case report of a 24-year-old male, smoker, with no other history, presented acutely, complaining of cool, painful hands with tricolour changes with worsening for 48 hours. On examination, apart from features of Raynaud’s and tender fingers, he had good perfusion, as shown by Doppler testing. Blood tests showed eosinophilia; 13x10*9 (Normal 0.04-0.40 x10*9) and mild raised C-reactive protein 24 (normal range <10.0 mg/L). Chest radiograph, ECG, and echocardiography showed no abnormalities. The results of initial screening including Immunoglobulins, complements, ANA, ANCA, RF, APLA and CCP were all negative. As there were no critical features of ischemia, we considered the patient for discharge from the hospital with a plan for close review. We strongly advised him not to smoke. He re-admitted within a week with worsening of Raynaud’s and features of critical ischemia with bluish nail and fingertip and some early features of mild digital necrosis. We began treatment with intravenous heparin, aspirin, and iloprost (prostacyclin) infusion for 10 days. The patient’s digital ischemia and intermittent claudication showed some improvement after 1 week, but eosinophilia persisted at 11x10*9 with ruminant pain in digits. The importance of smoking cessation was re-emphasised. Magnetic resonance angiography showed no occlusion of the distal arteries of the upper and lower extremities. Capillaroscopy showed micro haemorrhages (no connective tissue disease/scleroderma pattern abnormality). Investigations for parasitic infections and malignancy were negative. HIV / Hepatitis B/C CMV/EBV/Parvovirus IGM was all undetected. Schistosoma testing was negative. Haematology investigated him for the rare possibility of the genetic mutation for hypereosinophilic syndrome (PDGFRA and FIP1L1 genes) which was negative and underwent bone marrow biopsy which was also normal.We started him on oral prednisolone 1 mg/kg body weight with complete resolution of eosinophilia and ischemic symptoms plus Raynaud’s. Smoking stopped with help.DiscussionBuerger’s disease is a rare disease of exclusion and recognised as one form of vasculitis with a strong association with smoking and nicotine. There has been no consensus or any significant data for any specific therapies proven a benefit in this condition, more than in alone stopping smoking or even oral tobacco products. The main characteristic features of this form are present in young smokers with no systemic disease manifestation, normal inflammatory response, and negative immunology.Eosinophilia has only rarely been a feature of the presentation of Buerger’s disease. Its presence does not imply a systemic vasculitis or a related syndrome. Although there is limited evidence for the use of steroids in this condition, inflammatory features such as eosinophilia could strengthen the rationale for using steroids in certain cases by halting the ongoing immune driven inflammatory cascade. The presence of eosinophilia might suggest alternative pathogenic mechanisms in certain cases of Buerger’s.Key learning pointsTo recognise eosinophilia as a marker in atypical Buerger’s disease presentation. Being a disease of exclusion we have to rule out all other possibilities including some rare ones as was done in this case by seeking advice from infectious disease and haematology team.Conflicts of interestThe authors have declared no conflicts of interest.

Iloprost infusion prevents the insulin-induced reduction in skeletal muscle microvascular blood volume but does not enhance peripheral glucose uptake in type 2 diabetic patients.

In type 2 diabetes impaired insulin-induced muscle perfusion is thought to contribute to reduced whole-body glucose uptake. In this study, we examined the effects of iloprost, a stable prostacyclin analogue, on insulin-induced muscle capillary recruitment and whole-body glucose uptake. In a randomized cross-over design, 12 type 2 diabetes patients (age, 55 [46-69] years; BMI, 33.1 [31.0-39] kg/m2 ) underwent two hyperinsulinaemic-euglycaemic clamps, one with and one without simultaneous low-dose iloprost infusion. Contrast-enhanced ultrasonography of the vastus lateralis muscle was performed before and during the clamp. Muscle capillary recruitment was calculated as percentage change in microvascular blood volume (MBV) before and during the clamp. Insulin infusion reduced skeletal muscle MBV by ~50% compared to the fasting state (fasting, 1.77·10-4 [1.54·10-5 -2.44·10-3 ] arbitrary units (AU); hyperinsulinaemia, 6.69·10-5 [2.68·10-6 -5.72·10-4 ] AU; P = 0.050). Infusion of iloprost prevented this insulin-induced skeletal muscle capillary derecruitment, from (-49.5 [-89.5 to 55.3] %) to (8.0 [-68.8 to 306.6] %), for conditions without and with iloprost, respectively. The rate of glucose disappearance (Rd ) did not change significantly during iloprost infusion (17.3 [10.0-40.8] μmol/kg/min) compared with insulin infusion alone (17.6 [9.9-68.7] μmol/kg/min). Our data suggest that acute improvement in insulin-stimulated muscle perfusion is not an attractive therapeutic approach to bypass cellular resistance to glucose uptake in type 2 diabetes. Whether long-term improvements in insulin-induced muscle perfusion may prove beneficial for glucose disposal remains to be determined.

The safety of iloprost in systemic sclerosis in a real-life experience.

Iloprost (ILO) is employed intravenously for the treatment of severe Raynaud phenomenon (RP) and digital ulcers (DU) in systemic sclerosis (SSc). The aim of this study was to evaluate the safety and tolerability of the intravenous treatment with ILO in different phases of SSc. Eighty-one consecutive non-selected SSc patients, all on nifedipine, with moderate RP, treated with ILO infusion, were retrospectively evaluated. Patients were sub classified according to the edematous or fibrotic/atrophic cutaneous phase of the disease. ILO was infused with a progressive increase of the dosage up to the achievement of patient's tolerance, 1day/week. In cases of slower infusion regimen due to adverse events (AE) at the beginning of the administration, patients received a lower dose of the drug (not possible to quantify precisely the final cumulative dosage). 16/81 SSc patients presented digital edema, 5 developed diarrhea, and 9 developed transient hypotension during the infusion at 20ml/h that ameliorated when the drug was withdrawn. Moreover, 10/16 edematous patients experienced significant and painful digital swelling, unlike patients in the fibrotic group (p < 0.0001); 11/16 patients reported flushing and 7/16 headache, always controlled with dose tapering below 10ml/h. In the atrophic/fibrotic phase patients (65/81), 10 developed diarrhea and 24 hypotension at infusion rate of 20ml/h that led to temporary withdrawal of the drug. When ILO was restarted and kept below 10ml/h, no side effects were experienced. 23/65 patients experienced flushing and 8/65 headache, all controlled with infusion reduction below 10ml/h. In these patients, adverse events were significantly less frequent than in the edematous group (p = 0.023 and p = 0.008, respectively). Our data suggest that calcium channel blockers should be transitorily stopped while using ILO and that a pre-treatment approach might reduce or control adverse events. In patients with digital edema, ILO infusion should be carefully employed after the evaluation of patient's drug tolerance.

Evidence for increase in finger blood flow, evaluated by laser Doppler flowmetry, following iloprost infusion in patients with systemic sclerosis: a week-long observational longitudinal study

Objectives: Iloprost plays an important role in the treatment of Raynaud’s phenomenon (RP), but has transient vasodilatory effects owing to its very short half-time. We aimed to evaluate short- and medium-term haemodynamic effects of iloprost by measuring dorsal finger microvessel blood flow using laser Doppler flowmetry (LDF), in patients with RP associated with systemic sclerosis (SSc).Method: In 24 consecutive SSc patients with RP (disease duration 10.5 ± 1.3 years), LDF with heating probes was used to measure blood flow in four fingers by occlusive and heating tests, at baseline, after 3 consecutive days of iloprost infusion, and at 24 h and 7 days after last iloprost infusion. Nailfold videocapillaroscopy (NVC) patterns of microvascular damage were investigated. Sixteen healthy controls were studied to compare baseline flows.Results: Compared to controls, SSc patients showed significantly impaired axon reflex vasoregulation and nitric oxide responses at baseline (p = 0.001 and p = 0.03, respectively). After iloprost, a prompt but transient significant improvement in endothelial-dependent vasodilation (occlusive test) was seen only in SSc patients with an ‘active’ NVC pattern (p ≤ 0.05). The iloprost effects vanished within 7 days after the last infusion. No significant differences were found, in the whole study, between patients with and without digital ulcers.Conclusions: Microcirculatory blood flow increases following 3 days of iloprost infusion but fades shortly after treatment. Although iloprost is effective in reducing the severity of RP in SSc, the most suitable regimen and timing to obtain longer lasting vasodilatory benefits remain to be established.

BET 2: Treatment of frostbite with iloprost

A short cut review was carried out to establish whether an infusion of iloprost can be used to treat frostbite to reduce the risk of needing an amputation. Three studies...

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.

Capillary leakage, secondary to endothelial breakdown, is common in patients undergoing major surgical procedures with extensive tissue injury and this is associated with increased morbidity and mortality. Prostacyclin has been ascribed cytoprotective properties together with its vasodilatory and antiplatelet effects. The present pilot study investigated the safety and endothelial protective effects of low-dose prostacyclin infusion. A randomized placebo-controlled pilot study evaluating the effect of prostacyclin (iloprost) infusion (1.0 ng/kg/min) versus placebo (saline infusion) intraoperatively and 6 h postoperatively in patients undergoing a pancreaticoduodenoctemy was carried out. Hemodynamics were evaluated by Nexfin, hemostasis was evaluated by thrombelastography, and transfusion requirements were registered. Endothelial damage was evaluated by circulating sE-selectin, soluble thrombomodulin, and nucleosomes. Comparable baseline demography and surgical time were found. Hemodynamics were comparable between groups. The placebo group received more red blood cells, median 115 ml [interquartile range (IQR): 0-296 ml] versus 0 ml (IQR: 0-0 ml), P=0.027, at the postoperative ward and after 6 h. Thrombelastography maximum clot firmness decreased intraoperatively only in the placebo group (P=0.034)). Soluble thrombomodulin increased more in the placebo group postoperatively [1.63 ng/ml (IQR: 0.65-2.55 ng/ml) versus 0.40 ng/ml (IQR: 0.21-0.63 ng/ml), P=0.027] and 6 h postoperatively [1.83 (1.1-2.36) versus 0.67 (0.42-0.91), P=0.027]. Nucleosomes increased intraoperatively and postoperatively only in the placebo group; thus, the overall level of nucleosomes was higher in the placebo group (P=0.019). 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.

Investigation of Asymmetric and Symmetric Dimethylarginine Levels after Iloprost Treatment in Patients with Buerger's Disease

The aim of this study was to compare the levels of acetyl-dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), and the l-arginine/ADMA ratio before and after iloprost treatment in patients with Buerger's disease. Between January 2011 and December 2015, data from 44 patients (36 males, 8 females, mean age 48.7±18.1 years) with the diagnosis of Fontaine Stage III-IV Buerger's disease were included. Iloprost infusion was administered intravenously through the forearm veins for 7 days at a dose of 0.5-1.5ng/kg/min over 16h. Blood samples were collected before and after treatment for measurement of ADMA, SDMA, and l-arginine. ADMA, SDMA, l-arginine levels were measured using high performance liquid chromatography (HPLC). After iloprost treatment, ADMA and SDMA levels significantly decreased (p=.001). The increase in the l-arginine levels was not significant (p=.16). However, the l-arginine/ADMA ratio increased significantly (p=.001). Iloprost treatment decreases ADMA and SDMA, which are associated with endothelial dysfunctions in patients with Buerger's disease. Of note, the still higher than normal range of SDMA levels after iloprost treatment suggests that treatment should continue until SDMA levels are within the normal range in this patient population.

Digital ischemia and tobacco.

An active smoker 50-year-old male with precedents of arterial hypertension, consulted for a month history of pain and severe vasomotor disorder in the right hand. Physical exam revealed preserved radial pulse and severe cyanosis in all fingers, especially evolved in the fourth and fifth ones (A). Autoimmunity and hypercoagulability studies were requested and normal. An arteriogram of the right arm showed a corkscrew morphology of radial and ulnar arteries, without a complete refill of the palmar arches and with collateral circulation, typical findings of thromboangiitis obliterans (TAO), also known as Buerger's disease. In spite of smoking cessation and an initial improvement with intravenous iloprost and sildenafil infusions, the injuries kept on deteriorating. A thoracic sympathectomy was perform, which allowed to reduce the doses of opiate for pain control, but did not manage to avoid the amputation. TAO is a rare vascular, inflammatory and occlusive disease that affects the small to medium sized arteries, the distal veins and nerves of extremities. The etiology still remains unclear and it affects typically young smoking men. The only therapy that has demonstrated a constant benefit is smoking cessation. Other therapies frequently used are anticoagulants, vasodilators, antiplatelets and/or anti-inflammatories, although in most cases with a more palliative than curative purpose. Prognosis is favourable if patient quits smoking for good and the vessels damage is not too much evolved.