iloprost and Critical-Illness

Iloprost is a synthetic stable analogue of prostacyclin (PGI2), which shares its antiaggregating and vasodilating properties. Iloprost has been administered by i.v. route to patients with critical limb ischaemia (CLI) of different origin (maximal dosage: 2 ng/kg/min 6 hours/day infusion for 14-28 days). In patients with claudicatio intermittens (Fontaine stage II) iloprost improved the time to claudication and the maximal walking distance on treadmill, with an effect still lasting 60 days after suspension. This benefit was not related to a significant improvement in blood flow. Five multicentric, perspective, randomized versus placebo studies in patients with more severe CLI (Fontaine stage III-IV) susceptible to surgical treatment, showed that iloprost was able to reduce pain and ulcer dimensions. Furthermore, tha amputation rate of the ischemic limb was significantly lower in patients treated with iloprost during a 6 month follow-up (p < 0.01). Iloprost was also more effective than aspirin in causing pain relief and ulcer healing in patients with thromboangiitis obliterans and more effective than nifedipine in reducing frequency, intensity and duration of ischemic episodes in patients with Raynaud's phenomenon. Minor side effects of iloprost administration are represented by facial flushing, tachycardia, headache, nausea, vomiting, abdominal cramping, diarrhoea, whose frequency ranges from 16% to 70%; major collateral effects, occurring in less than 5% of patients, are above all represented by severe hypotension and angina pectoris. Clinical data indicate therefore that iloprost treatment can allow to improve the clinical conditions and the prognosis in patients with critical ischemia of the limbs, not candidate to surgical revascularization, by causing a relief of pain, a reduction in ulcer dimensions and deferring amputation.

Topics: Clinical Trials as Topic; Critical Illness; Humans; Iloprost; Ischemia; Leg

Use of prostanoids in vascular surgery is valuable in various conditions: intra and postoperatively, during limb salvage procedures, they are useful to lower peripheral resistances, and in patients with limited gangrene, when surgery is not feasible, they improve limb blood flow. After some years of subjective clinical evaluation, multicentric randomized clinical trials started; the aim was to quantify the real benefit derived from the use of prostanoids to the evolution of limb ischemia and to the improvement of results of surgical revascularization. We have not yet definitive results; preliminary data show a better immediate patency rate of femoro-distal bypass grafts and a critical reduction in long term limb amputations.

Topics: Clinical Trials as Topic; Critical Illness; Humans; Iloprost; Intraoperative Care; Ischemia; Leg; Salvage Therapy

Platelets critically contribute to atherothrombosis and worsening ischaemia in patients with peripheral arterial disease (PAD), eventually leading to critical limb ischaemia (CLI). Furthermore, persistent platelet activation despite antiplatelet therapy has been reported in this setting. The prostacyclin analogue iloprost is currently recommended in CLI patients for its effects in relieving symptoms by promoting local perfusion. In this study, we investigated the effects of iloprost infusion on urinary 11-dehydro-TXB₂ and 8-iso-PGF(₂α) excretion rate, as in vivo indexes of thromboxane-dependent platelet activation and lipid peroxidation, respectively, and on platelet-derived proinflammatory sCD40L and nitric oxide bioavailability in 44 patients with CLI while on chronic treatment with low-dose aspirin. Daily iloprost infusion for one-week significantly decreased urinary 11-dehydro-TXB₂ [499 (277-807) vs. 380 (189-560) pg/mg creatinine, p < 0.0001] and 8-iso-PGF(₂α) [533 (316-842) vs. 334 (196-540) pg/mg creatinine, p < 0.0001] as well as plasma sCD40L [1540 (1005-3015) vs. 948 (845-2030) pg/ml, p < 0.0001]. Furthermore, a significant increase in plasma nitrate plus nitrite levels has been observed [26.8 (18.8-35.9) vs. 43.7 (33.0-75.5) μM, p < 0.0001]. A significant direct correlation was also found between urinary 8-iso-PGF(₂α) and 11-dehydro-TXB2 before and after iloprost treatment (Rho = 0.695, p < 0.0001). In conclusion, we report that a short-term course of iloprost is able to significantly reduce residual thromboxane biosynthesis, oxidative stress, endothelial dysfunction and platelet-derived inflammation in low-dose aspirin treated patients with CLI.

Topics: Aged; Aged, 80 and over; Aspirin; Biomarkers; Blood Platelets; CD40 Ligand; Chi-Square Distribution; Critical Illness; Dinoprost; Drug Administration Schedule; Female; Humans; Iloprost; Inflammation Mediators; Infusions, Intravenous; Ischemia; Italy; Lipid Peroxidation; Male; Middle Aged; Nitric Oxide; Oxidative Stress; Platelet Activation; Platelet Aggregation Inhibitors; Thromboxane B2; Time Factors; Treatment Outcome

Patients with critical limb ischemia (CLI) have low levels of endothelial progenitor cells (EPC). Iloprost has been demonstrated to stimulate vascular endothelial growth factor (VEGF) and promote angiogenesis. We investigated the effects of iloprost on EPC levels in vivo in CLI patients. Twenty-three patients with stage III and IV CLI were treated with iloprost for four weeks, improving clinical and instrumental parameters. Mononuclear cells isolated from peripheral blood were cultured to obtain "early" EPC, evaluated counting adherent cells with double positivity for acetylated low-density lipoprotein uptake and Ulex Europaeus lectin at flow cytometry. These cells also co-expressed the monocyte markers CD14 and CD45. Iloprost increased EPC number in the whole patient population: pre-treatment median: 13,812/ml; range: 1,263-83,648/ml; post-treatment median: 23,739/ml; range: 3,385-99,251/ml; p = 0.035, irrespective of age, sex, disease stage or atherosclerosis risk factors. In conclusion, iloprost increases EPC number in peripheral blood in vivo. Such an effect may have therapeutic relevance.

Topics: Aged; Aged, 80 and over; Angiogenesis Inducing Agents; Carbon Dioxide; Cells, Cultured; Critical Illness; Endothelial Cells; Extremities; Female; Humans; Iloprost; Infusions, Intravenous; Intermittent Claudication; Ischemia; Male; Oxygen; Stem Cells; Treatment Outcome; Vascular Endothelial Growth Factor A

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.

Topics: Aged; Cardiovascular Agents; Critical Illness; Female; Humans; Iloprost; Ischemia; Lymphocyte Count; Lymphocytes; Male; Middle Aged; Neutrophils; Peripheral Arterial Disease; Predictive Value of Tests; Retrospective Studies; Risk Assessment; Risk Factors; Time Factors; Treatment Outcome; Wound Healing

Topics: Administration, Intravenous; Aged; Angioplasty, Balloon; Cardiovascular Agents; Coated Materials, Biocompatible; Critical Illness; Drug Administration Schedule; Female; Humans; Iloprost; Ischemia; Lower Extremity; Male; Middle Aged; Peripheral Arterial Disease; Retrospective Studies; Time Factors; Treatment Outcome; Vascular Access Devices; Wound Healing

Previous studies demonstrated that early recoil is frequently observed in patients undergoing balloon angioplasty. The aim of this study was to evaluate the impact of intra-arterial administration of iloprost (Endoprost®, Italfarmaco S.p.A., Milan, Italy) on early elastic recoil after balloon angioplasty of below-the-knee (BTK) vessels in patients with critical limb ischemia (CLI).. Between January 2015 and December 2015 32 patients with CLI underwent balloon angioplasty of at least one BTK vessel followed by intra-arterial administration of iloprost. Early elastic recoil was defined as residual lumen compromise >10%. Early elastic recoil was determined on the basis of minimal lumen diameter (MLD) measurements at baseline (MLDbaseline), immediately after BTK balloon angioplasty (MLDpostdilation), and 15 minutes thereafter (MLD15min).. Patients were predominantly female (18/32, 56.2%) with a mean age of 79.6 years (range 68-87). Most of the patients were diabetics (25/32, 78.1%). An occlusion was present in 24 cases (75%). Mean BTK lesion length was 144.1 mm (range 22-320). Mean MLD measurements were 0.1 mm (range 0-0.5; MLDbaseline), 2.5 mm (range 1.9-3; MLDpostdilation), and 1.9 mm (range 0.7-3; MLD15min). Early elastic recoil was recorded in 14 patients (43.8%). The mean percentage of elastic recoil after 15 minutes was 21.4%.. In our experience intra-arterial administration of iloprost reduces the risk of early elastic recoil after balloon angioplasty of BTK vessels in patients with CLI. Further analyses with larger population studies and randomized trials are needed to validate this therapeutic option.

Topics: Aged; Aged, 80 and over; Angioplasty, Balloon; Critical Illness; Elasticity; Female; Humans; Iloprost; Injections, Intra-Arterial; Ischemia; Leg; Male; Peripheral Arterial Disease; Recurrence; Time Factors; Treatment Outcome; Vascular Patency; Vasodilator Agents

Proper management of patients with thromboangiitis obliterans (TAO) or cannabis-associated arteritis (CAA), presenting with critical lower limb ischaemia (CLI) remains controversial, and data are limited.. Patients with TAO or CAA presenting with CLI between 2011 and 2016 were retrospectively evaluated. Patients requiring primary intervention were excluded. Conservative treatment included: (a) weight-adjusted bemiparin plus six hours/day intravenous iloprost for 28 days, (b) aspirin (100 mg/day) plus cilostazol (100 mg twice/day) after discharge, and (c) strict recommendations/monitoring for smoking cessation. Main outcomes included symptom recession, ankle-brachial index (ABI) improvement, and healing of lesions at the time of discharge as well as amputation, revascularization, and abstinence rate during follow-up.. Overall, 23 patients (TAO: 15; CAA: 8) were included within six years, none of the patients reported any other factor than smoking. All patients presented with rest pain and 12 patients with ulcer or necrotic lesions. Mean ABI measurement at presentation was 0.46 ± 0.2, after 28 days of treatment, all patients showed improvement regarding clinical picture and ABI measurement (0.54 ± 0.1; p < 0.05). During follow-up, only three patients underwent bypass surgery and two patients underwent major amputation, although the smoking abstinence rate was very low (13 %).. Intravenous iloprost plus bemiparin for 28 days together with per os aspirin plus cilostazol seem to produce promising results in patients with TAO/CAA, treated for CLI, even with a low smoking abstinence rate. However, larger series are needed to further evaluate inter-group differences and potential prognostic factors.

Topics: Adult; Amputation, Surgical; Ankle Brachial Index; Anticoagulants; Arteritis; Aspirin; Cardiovascular Agents; Cilostazol; Critical Illness; Drug Therapy, Combination; Female; Heparin, Low-Molecular-Weight; Humans; Iloprost; Infusions, Intravenous; Ischemia; Limb Salvage; Lower Extremity; Male; Marijuana Abuse; Marijuana Smoking; Middle Aged; Platelet Aggregation Inhibitors; Recurrence; Remission Induction; Retrospective Studies; Risk Factors; Smoking; Smoking Cessation; Tetrazoles; Thromboangiitis Obliterans; Time Factors; Treatment Outcome; Vasodilator Agents

Whether medical therapy alone may reduce the amputation rates in patients with chronic limb ischemia and who are unsuitable for revascularization is a controversial topic. In this study, we aimed to investigate the effects of 1 week infusion of iloprost in the treatment of patients with chronic limb ischemia.. Twenty-seven consecutive patients were included in the study. There were 23 men (85.2%) and 4 women (14.8%) with a mean age of 68.93 ± 14.84 years. Patients were considered eligible if they were unsuitable for surgical and endovascular revascularization. Follow-up was made on 10th day and 6th month and included ankle brachial index and clinical assessment.. Minor side effects occurred in four patients (16.0%), but the treatment was continued. In-hospital mortality occurred in one patient (4.0%). Another two patients died and four patients received amputation until follow-up (overall mortality 11.1%). There was significant increase in mean ankle-brachial index values between 1st day and 10th day (p < 0.001), between 1st day and 6th month (p < 0.001), and between 10th day and 6th month (p < 0.001).. One-week treatment with iloprost may provide both long lasting symptomatic benefit and may improve hemodynamic parameters, which were shown to predict future amputation.

Topics: Adult; Aged; Aged, 80 and over; Amputation, Surgical; Ankle Brachial Index; Chronic Disease; Critical Illness; Drug Administration Schedule; Endovascular Procedures; Female; Hospital Mortality; Humans; Iloprost; Infusions, Intravenous; Ischemia; Lower Extremity; Male; Middle Aged; Prospective Studies; Risk Factors; Time Factors; Treatment Outcome; Vascular Surgical Procedures; Vasodilator Agents

To assess the efficacy and of iloprost in the treatment of Buerger's disease.. In this prospective study, 158 patients with rest pain and/or ischemic ulcers from 17 clinics were administered 1 ng/kg/min intravenous iloprost for 28-days. The primary endpoint was complete healing without pain or major amputation at 24 weeks. The secondary endpoints were pain assessment, reduction in ulcer area, 50% reduction of the ulcer size, shift in the modified SVS/ISCVS clinical status grading scale, global assessment by the investigator and an independent observer at 4 and 24 weeks. The comparisons were carried out with the initial values. The final evaluation was carried out in 150 patients.. Complete healing rate was significantly better with iloprost treatment in comparison to the initial values at 24 weeks (<0.001). The secondary endpoints; complete healing rate, pain, the size of the ulcer, 50% reduction of the ulcer size, SVS/ISCVS grading scale, assessment by investigator, assessment by observer parameters were significantly better at 4 and 24 weeks (<0.001). The reduction of the ulcer size was significantly better when comparing 4th and 24th week values (<0.05).. The results of this independent study indicate that intravenous iloprost relieves ischemic symptoms efficiently in the acute phase Buerger's disease patients. Considering unsatisfactory results following surgical revascularisation and sympathectomy in Buerger's disease, prostacyclin analogues might be the first line treatment as long as complete abstinence from smoking is achieved.

Topics: Adult; Amputation, Surgical; Analysis of Variance; Chi-Square Distribution; Critical Illness; Female; Humans; Iloprost; Infusions, Intravenous; Ischemia; Male; Middle Aged; Pain; Prospective Studies; Smoking; Smoking Cessation; Smoking Prevention; Thromboangiitis Obliterans; Time Factors; Treatment Outcome; Turkey; Wound Healing

Aerosolized iloprost, an inhaled synthetic analogue of prostacyclin, is an approved therapy for stage III and IV pulmonary hypertension. However, currently iloprost is delivered via a device that requires a clinically stable patient who can use a hand-held nebulizer. We designed separate aerosol delivery systems to nebulize iloprost to critically ill patients during (1) mechanical ventilation and (2) spontaneous breathing that requires a high fraction of inspired oxygen. The goal was to deliver doses similar to the currently approved high-efficiency I-neb nebulizer system.. For the intubated patient we used the high-efficiency AeroTech II jet nebulizer and a breath-actuated ventilator circuit, without humidification. For spontaneous breathing, our delivery system consisted of a Pulmanex Hi-Ox disposable oxygen mask and an AeroTech II nebulizer. With a nebulizer charge of 20 microg, the drug presented to the patient (inhaled mass) was captured on a filter and analyzed using radioactivity (technetium-99m). The accuracy of the radiolabel was quantified by directly measuring iloprost with high-performance liquid chromatography and comparing the results. A cascade impactor measured particle distribution.. A line of identity confirmed that the radiolabel accurately represented the drug. The mean +/- SD inhaled mass was 6.02 +/- 0.87 microg (n = 5) on the ventilator and 3.77 +/- 0.46 microg (n = 5) during spontaneous ventilation. The mass median aerodynamic diameter and fine-particle fraction were 0.7 microm, 0.99, and 0.7 microm, 0.99, respectively.. Clinically effective doses of iloprost can be delivered to patients who require high-flow oxygen or mechanical ventilation.

Topics: Administration, Inhalation; Aerosols; Chromatography, High Pressure Liquid; Critical Illness; Equipment Design; Humans; Hypertension, Pulmonary; Iloprost; Masks; Nebulizers and Vaporizers; Vasodilator Agents

The aim of this study was to evaluate the capacity of transcutaneous partial pressure of O(2) (TCpO(2)) and CO(2) (TCpCO(2)) to predict clinical response to pharmacological treatment in short- and long-term follow-up of unreconstructable critical limb ischemia (CLI) treated with prostanoids; to suggest a diagnostic and therapeutic algorithm able to define the possibility of prostanoid therapy in unreconstructable CLI at high risk of limb loss.. Twenty-six consecutive patients with CLI (21 with distal trophic lesions, 31 symptomatic limbs) considered unreconstructable after peripheral angiography and with a history of type 2 diabetes mellitus underwent daily parenteral Iloprost treatment for 2-3 weeks.. Transcutaneous gas-analytic monitoring (TGM) in non-reconstructable CLI treated with Iloprost divided patients into 2 groups: early responders (ER) with increased TcpO(2) and normalization of TcpCO2, and non responders (NR) with unchanged TcpO(2) and TcpCO(2) parameters. In the NR who underwent a second cycle of Iloprost within a few months of the first, TGM further divided the patients into another subgroup of late responders (LR) with TcpO(2) and TcpCO(2) similar to the ER group and a subgroup of NR, who, after pharmacological treatment failure, should undergo eventual surgical re-timing and/or spinal cord stimulation in a final attempt to save the limb.. In the short-term follow-up of CLI, a marked reduction in supine/dependent TcpO(2) and a marked increase in supine TcpCO(2) at the symptomatic forefoot proved to be significant predictors of major amputation risk. In the long-term follow-up period, TGM showed that, in ER and in LR, the favourable effect of pharmacological therapy observed in the first 6 months will disappear over the next 6 months, suggesting an algorithm of 2- to 3-week cycles of prostanoid therapy repeated every year. In NR treated with surgical and/or alternative therapies who did not undergo major amputations, prolonged instrumental TGM will provide a constant evaluation of metabolic parameters, thus providing the possibility to save the limb with additional pharmacological therapy.

Topics: Aged; Aged, 80 and over; Blood Gas Monitoring, Transcutaneous; Critical Illness; Female; Humans; Iloprost; Ischemia; Leg; Male; Middle Aged; Time Factors; Vasodilator Agents

The authors, after examination of pharmacologic profile of Iloprost, prostacyclin synthetic analogue, report their clinical experience from January 1992 to June 1997 on 105 patients with severe ischaemia of inferior limbs. They utilize two protocols: 0.5-2 ng/kg/min x 6 hs once a day x 28 days and 1-1.5 ng/kg/min x 6 hs twice a day x 12 days. The first protocol were practise along the first 2 years; the second on following period as long as today. The results, evaluated on clinical criteria, are referred entity and time of pain remission and decrease of analgesic use, performance status improvement, increase of gear autonomy and, if present, wound healing. The incidence of amputation was 4.76% (5 pts). The authors issue that Iloprost is a conservative treatment, often alternative with amputation, giving sometimes to patients a longtime functional "restitutio ad integrum".

Topics: Arterial Occlusive Diseases; Critical Illness; Diabetic Angiopathies; Follow-Up Studies; Humans; Iloprost; Infusion Pumps; Ischemia; Leg; Treatment Outcome; Vasodilator Agents

Topics: Critical Illness; Hemodynamics; Humans; Iloprost; Infusions, Intravenous; Oxygen; Respiratory Insufficiency; Veins