Prostacyclin Infusion Research Articles

Dual prostacyclin infusions: A case report of a patient symptom-driven transition from high-dose intravenous epoprostenol to subcutaneous treprostinil for the treatment of pulmonary arterial hypertension.

In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. A case of successful transition from high-dose epoprostenol to high-dose subcutaneous treprostinil for treatment of pulmonary arterial hypertension (PAH) is reported. PAH is a chronically progressive disease characterized by pulmonary artery luminal narrowing that causes increased pulmonary artery pressures leading to right ventricular failure. Parenteral prostacyclin analogues, such as epoprostenol and treprostinil, are direct vasodilators and are cornerstones of therapy for patients with severe disease that have been proven to reduce mortality and increase exercise tolerance. These agents must be administered continuously via intravenous or subcutaneous devices and are high-risk medications due to their potent vasodilatory actions. Chronic use of these medications requires constant attention from both providers and patients because of potential complications including central venous catheter infection, thromboembolism, therapy interruptions, and other undesirable consequences. This case report describes management of a 35-year-old male patient on high-dose outpatient intravenous epoprostenol (101ng/kg/min; dosing weight, 47kg) for treatment of PAH who was admitted to the hospital with a malfunctioning central venous catheter. Surrounding manipulation of the central catheter, the patient experienced an ischemic stroke that led to cognitive disability resulting in a lack of ability to manage his previously used home infusion device. The patient was successfully transitioned from intravenous epoprostenol to subcutaneous treprostinil (discharge dose, 200ng/kg/min) over 5 days by infusing both medications simultaneously and adjusting doses based upon patient-reported symptoms. This successful transition from high-dose epoprostenol to high-dose subcutaneous treprostinil demonstrates the importance in considering patient-specific factors during high-risk medication transitions, the value of a patient-directed flexible prostacyclin transition plan, and the benefit of institutional training and education in ensuring the safe use of parenteral prostacyclin analogues.

Two polymorphic gene loci associated with treprostinil dose in pulmonary arterial hypertension.

Prostacyclin infusion for pulmonary arterial hypertension (PAH) is an effective therapy with varied dosing requirements and clinical response. The major aim of this study was to determine new biologically-based predictors of prostacyclin treatment response heterogeneity. Ninety-eight patients with hemodynamically defined PAH at two academic medical centers volunteered for registry studies. A stable dose of treprostinil was the quantitative phenotype for the genome-wide association study (GWAS). Candidate genes with the largest effect sizes and strongest statistical associations were further characterized with in silico and in-vitro assays to confirm mechanistic hypotheses. The clinical significance of these candidate predictors was assessed for mechanistically consistent physiologic effects in an independent cohort of patients. GWAS identified three loci for association with P < 10-6. All three loci had clinically significant effect sizes. Specific single-nucleotide polymorphisms (SNPs) at two of the loci: rs11078738 in phosphoribosylformylglycinamidine synthase and rs10023113 in CAMK2D encoded sequence changes with clear predicted consequences. Production of the primary mediator of prostacyclin-induced vasodilation, cyclic AMP, was reduced in human cell lines by the missense variant rs11078738 (p.L621P). Located in the promoter of CAMK2D, the allele of rs10023113 associated with a higher treprostinil dose has higher ventricular transcription of CAMK2δ. At initial diagnostic catheterization in a separate cohort of patients, the same allele of rs10023113 was associated with elevated right mean atrial and ventricular diastolic pressures. The quantitative phenotype of stable treprostinil dose identified two gene loci associated with pharmacodynamic response and right ventricular function in PAH worth further investigation.

The effect of prostacyclin infusion on markers of endothelial activation and damage in mechanically ventilated patients with SARS-CoV-2 infection.

BackgroundIn a pilot study, we found a significant reduction in mean daily sequential organ failure assessment score in mechanically ventilated patients with COVID-19 who received prostacyclin, compared to placebo. We here investigate the effect on biomarkers of endothelial activation and damage.MethodsPost-hoc study of a randomized controlled trial in adult patients with confirmed SARS-CoV-2 infection, mechanically ventilated, with soluble thrombomodulin (sTM) plasma levels >4 ng/mL. Patients received prostacyclin infusion (1 ng/kg/min) or placebo. Blood samples were collected at baseline and 24 h.ResultsEighty patients were randomized (41 prostacyclin, 39 placebo). The median changes in syndecan-1 plasma levels at 24 h were −3.95 (IQR: −21.1 to 2.71) ng/mL in the prostacyclin group vs. 3.06 (IQR: −8.73 to 20.5) ng/mL in the placebo group (difference of the medians: -7.01 [95% CI: −22.3 to −0.231] ng/mL, corresponding to −3% [95% CI: −11% to 0%], p = 0.04). Changes in plasma levels of sTM, PECAM-1, p-selectin, and CD40L did not differ significantly between groups.ConclusionsProstacyclin infusion, compared to placebo, resulted in a measurable decrease in endothelial glycocalyx shedding (syndecan-1) at 24 h, suggesting a protective effect on the endothelium, which may be related to the observed reduction in organ failure.

Prostacyclin in Intubated Patients with COVID-19 and Severe Endotheliopathy: A Multicenter, Randomized Clinical Trial.

RationaleThe mortality in patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) who require mechanical ventilation remains high, and endotheliopathy has been implicated.ObjectivesTo determine the effect of prostacyclin infusion in mechanically ventilated patients infected with SARS-CoV-2 with severe endotheliopathy.MethodsWe conducted a multicenter, randomized clinical trial in adults infected with coronavirus disease (COVID-19) who required mechanical ventilation and had a plasma level of thrombomodulin >4 ng/ml; patients were randomized to 72-hour infusion of prostacyclin 1 ng/kg/min or placebo.Measurements and Main ResultsThe main outcome was the number of days alive and without mechanical ventilation within 28 days. Key secondary outcomes were 28-day mortality and serious adverse events within 7 days. Eighty patients were randomized (41 prostacyclin and 39 placebo). The median number of days alive without mechanical ventilation at 28 days was 16.0 days (SD, 12) versus 5.0 days (SD, 10) (difference of the medians, 10.96 days; 95% confidence interval [CI], −5 to 21; P = 0.07) in the prostacyclin and the placebo groups, respectively. The 28-day mortality was 21.9% versus 43.6% in the prostacyclin and the placebo groups, respectively (risk ratio, 0.50; 95% CI, 0.24 to 0.96; P = 0.06). The incidence of serious adverse events within 7 days was 2.4% versus 12.8% (risk ratio, 0.19; 95% CI, 0.001 to 1.11; P = 0.10) in the prostacyclin and the placebo groups, respectively.ConclusionsProstacyclin was not associated with a significant reduction in the number of days alive and without mechanical ventilation within 28 days. The point estimates, however, favored the prostacyclin group in all analyses, including 28-day mortality, warranting further investigation in larger trials.Clinical trial registered with www.clinicaltrials.gov (NCT 04420741); EudraCT Identifier: 2020-001296-33.

Pulmonary-to-Systemic Arterial Shunt to Treat Children With Severe Pulmonary Hypertension

BackgroundThe placement of a pulmonary-to-systemic arterial shunt in children with severe pulmonary hypertension (PH) has been demonstrated, in relatively small studies, to be an effective palliation for their disease. ObjectivesThe aim of this study was to expand upon these earlier findings using an international registry for children with PH who have undergone a shunt procedure. MethodsRetrospective data were obtained from 110 children with PH who underwent a shunt procedure collected from 13 institutions in Europe and the United States. ResultsSeventeen children died in-hospital postprocedure (15%). Of the 93 children successfully discharged home, 18 subsequently died or underwent lung transplantation (20%); the mean follow-up was 3.1 years (range: 25 days to 17 years). The overall 1- and 5-year freedom from death or transplant rates were 77% and 58%, respectively, and 92% and 68% for those discharged home, respectively. Children discharged home had significantly improved World Health Organization functional class (P < 0.001), 6-minute walk distances (P = 0.047) and lower brain natriuretic peptide levels (P < 0.001). Postprocedure, 59% of children were weaned completely from their prostacyclin infusion (P < 0.001). Preprocedural risk factors for dying in-hospital postprocedure included intensive care unit admission (hazard ratio [HR]: 3.2; P = 0.02), mechanical ventilation (HR: 8.3; P < 0.001) and extracorporeal membrane oxygenation (HR: 10.7; P < 0.001). ConclusionsA pulmonary-to-systemic arterial shunt can provide a child with severe PH significant clinical improvement that is both durable and potentially free from continuous prostacyclin infusion. Five-year survival is comparable to children undergoing lung transplantation for PH. Children with severely decompensated disease requiring aggressive intensive care are not good candidates for the shunt procedure.

PH Professional Network: The Benefits and Challenges in Delivering Telehealth in Pediatric Pulmonary Hypertension

PH Professional Network: The Benefits and Challenges in Delivering Telehealth in Pediatric Pulmonary Hypertension

Triple oral combination therapy with macitentan, riociguat, and selexipag for pulmonary arterial hypertension.

Background:The evidence regarding triple oral combination therapy for patients with pulmonary arterial hypertension (PAH) is scarce. This study was performed to investigate the effectiveness and safety of triple oral combination therapy with macitentan, riociguat, and selexipag.Methods:Among consecutive patients with PAH who were referred to our hospital from 2009 to 2020, those who underwent triple oral combination therapy using macitentan, riociguat, and selexipag were retrospectively analyzed. Hemodynamic and echocardiographic assessments and Kaplan–Meier analyses of all-cause death and initiation of prostacyclin infusion were conducted.Results:Twenty-six patients underwent this combination therapy. These patients were predominantly female (73.1%) with a median age of 38 years at baseline and nine patients were taking some PAH medications at baseline. The median time from initiation of the first PAH drug to the third PAH drug in treatment naïve patients was 24 days (interquartile range, 12–47 days). Four patients (15.0%) discontinued taking any of the three vasodilators because of adverse events, and 17 patients (65.4%) reached the maximum dose of all three drugs. The mean pulmonary arterial pressure, pulmonary vascular resistance, and cardiac output improved by 29%, 65%, and 82%, respectively (median observation period: 441 days) and similar improvements were observed in treatment-naïve patients at baseline. The survival rate and prostacyclin infusion-free rate since administration of all three vasodilators was 93.3% and 74.6% at 3 years, respectively. When patients were divided by risk stratification, the prostacyclin-free rate at 3 years was 92.9% in low-/intermediate-risk patients and 55.0% in high-risk patients.Conclusion:Triple oral combination therapy with macitentan, riociguat, and selexipag sufficiently improved clinical parameters and was well tolerated in patients with PAH. This combination could be a particularly promising strategy in patients with low/intermediate risk and possibly even in half of patients with high risk. Further studies are needed to validate these findings. The reviews of this paper are available via the supplemental material section.

Prevention of Acquired Transient Defect in Platelet Plug Formation by Infused Prostacyclin

AbstractCardiopulmonary bypass in baboons produced transient severe platelet dysfunction (bleeding times prolonged to 27.8 ±1.4 min compared with 3.9 ± 0.7 baseline) that was associated with a parallel release of platelet α-granule proteins into plasma (platelet factor 4 and β-thromboglobulin levels of 28.8 ± 9.3 and 20.0 ±1.8 ng/ml, respectively) and their clearance into urine with a reciprocal depletion from circulating platelets. In contrast, plateletdense granules did not undergo significant release. The bleeding times normalized rapidly following bypass (8.5 ± 1.4 min at 1 hr). The infusion of prostacyclin (PGI2) into the bubble oxygenator during bypass (40–80 ng/kg/min) prevented the prolongation in bleeding time (p < 0.01 compared with untreated control values) but did not block the release of α-granule proteins. Dosages outside this range were associated with prolonged bleeding times. These results show that transient platelet dysfunction occurring during cardiopulmonary bypass represents activation of platelets independent of α or dense granule release and is blocked by potent short-acting inhibition of platelet function using PGI2 infused into the oxygenator apparatus at optimal therapeutic doses.

Management of hospitalized patients with pulmonary arterial hypertension and COVID-19 infection.

Management of hospitalized patients with pulmonary arterial hypertension and COVID-19 infection.

Buerger’s disease or thromboangiitis obliterans: description of two cases

Buerger’s disease, or thromboangiitis obliterans (TAO), is a segmental non-atherosclerotic occlusive inflammatory condition of small arteries and veins of the upper and lower extremities, characterized by thrombosis and recanalization of the affected vessels. It is triggered by substantial exposure to tobacco, especially in males aged from 20 to 50. Currently, the most effective treatment, together with the suspension of the smoking habit, is represented by prostacyclin infusion (Iloprost). We described two cases of Buerger’s disease recently presented to our observation, with some different clinical features and therapeutic pathways.

Infusion of Prostacyclin (Iloprost) vs Placebo for 72-hours in Patients With Septic Shock Suffering From Organ Failure

Infusion of Prostacyclin (Iloprost) vs Placebo for 72-hours in Patients With Septic Shock Suffering From Organ Failure

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.

EXPRESS: Transition from Parental Prostacyclin to Selexipag: A Case Series of Five Pulmonary Arterial Hypertension Patients.

Parental prostacyclin is the only therapy with a proven survival benefit in pulmonary arterial hypertension (PAH). However, some patients are unable to tolerate continuous prostacyclin infusion because of central line infection, side effects, or sociocultural factors. Selexipag is a recently approved prostacyclin receptor agonist that is able to blunt PAH disease progression. Although in the same molecular pathway, the interchangeability of selexipag with prostacyclin infusions is relatively unexplored. Here, we present a case series of five stable PAH patients who were functional class (FC) I or II that were transitioned from prostacyclin infusion to selexipag using a standardized protocol in the inpatient setting. We show that the transition to selexipag in five highly selected patients was tolerated with no significant changes in FC, minimal changes in pulmonary vascular disease severity, and no significant PAH-related complications. However, there was a trend for a reduction in cardiac index after transition to selexipag. These data suggest that a transition from prostacyclin infusion to selexipag can be achieved in clinically stable PAH patients who are unable to tolerate continuous prostacyclin infusion. However, this approach should only be selectively implemented at specialized centers with close follow-up due to the trend for a reduction in cardiac index after transition to selexipag.

Two Polymorphic Gene Loci Associated with Treprostinil Dose in Pulmonary Arterial Hypertension

Purpose Prostacyclin infusion is an effective therapy for pulmonary arterial hypertension (PAH) but has variable clinical response and dosing requirements. We performed a genome-wide association study (GWAS) to identify biologically-based predictors of prostacyclin response heterogeneity and gene variants associated with PAH pathogenesis . Methods Ninety-eight patients with hemodynamically-defined PAH treated at two academic centers were included. Stably dosed treprostinil therapy was the quantitative phenotype for the GWAS. Candidate genes with the largest effect sizes and strongest statistical associations were further characterized in silico and in vitro to confirm mechanistic hypotheses, and at cardiac catheterization to assess for mechanistically consistent physiological effects. Results Three loci associated with treprostinil dose with P encoded sequence changes with predictable consequences. Production of the prostacyclin-induced pulmonary vasodilator cyclic adenosine monophosphate was reduced in human cell lines by the missense variant rs11078738. The allele of rs10023113 in the promoter of CAMK2D associated with higher treprostinil dose, conferred a reduced affinity for the FOXP1 transcriptional repressor , was associated with increased expression of CAMKIIδ in ventricular tissue, and was associated with elevated right mean atrial and ventricular diastolic pressures in a separate cohort of patients at cardiac catheterization. Conclusion The conduct of effective GWAS is challenging with small numbers of patients. However, by employing the quantitative phenotype of stable treprostinil dose we identified 2 novel loci for treatment response in PAH, gene variants associated with more severe right ventricular dysfunction and higher ultimate dose of treprostinil. Work is ongoing to further characterize these variants.

Aerobic exercise training lowers platelet reactivity and improves platelet sensitivity to prostacyclin in pre‐ and postmenopausal women

Background The risk of atherothrombotic events increases after the menopause. Regular physical activity has been shown to reduce platelet reactivity in younger women, but it is unknown how regular exercise affects platelet function after the menopause. Objectives To examine the effects of regular aerobic exercise in late premenopausal and recent postmenopausal women by testing basal platelet reactivity and platelet sensitivity to prostacyclin and nitric oxide. Methods Twenty-five sedentary, but healthy, late premenopausal and 24 matched recently postmenopausal women, mean (95% confidence interval) 49.1 (48.2-49.9) and 53.7 (52.5-55.0) years old, participated in an intervention study: 3-month high-intensity supervised aerobic spinning-cycle training (1 h, × 3/week). Basal platelet reactivity was analyzed in platelet-rich plasma from venous blood as agonist-induced % aggregation. In a subgroup of 13 premenopausal and 14 postmenopausal women, platelet reactivity was tested ex vivo after femoral arterial infusion of prostacyclin, acetylcholine, a cyclooxygenase inhibitor, and after acute one-leg knee extensor exercise. Results Basal platelet reactivity (%aggregation) to TRAP-6 (1 μm) was higher in the postmenopausal, 59% (50-68), than the premenopausal women, 45% (35-55). Exercise training reduced basal platelet reactivity to collagen (1 μg mL-1 ) in the premenopausal women only: from 63% (55-71%) to 51% (41-62%). After the training intervention, platelet aggregation was more inhibited by the arterial prostacyclin infusion and the acute exercise in both premenopausal and postmenopausal women. Conclusions These results highlight previously unknown cardioprotective aspects of regular aerobic exercise in premenopausal and postmenopausal women, improving their regulation of platelet reactivity through an increased platelet sensitivity to prostacyclin, which may counterbalance the increased atherothrombotic risk associated with the menopause.

Effect of delayed onset prostacyclin on markers of endothelial function and damage after subarachnoid hemorrhage.

Subarachnoid hemorrhage (SAH) is a neurological emergency. Delayed ischemic neurological deficit is one of the main causes of poor outcome after SAH and is probably caused, at least in part, by cerebral vasospasm. The pathophysiology of this is multifaceted, but endothelial damage and activation as well as glycocalyx damage have been implicated. Prostacyclin has been shown to protect damaged and activated endothelium and to facilitate glycocalyx repair. We investigated biomarkers of endothelial activation and damage in patients with SAH randomized to 5days prostacyclin infusion or placebo. Patients with aneurysmal SAH managed by coiling or surgery, and a World Federation of Neurological Surgeons score between 1 and 4, and Fisher grade 3 or 4, were treated with a continuous low-dose intravenous prostacyclin infusion or placebo initiated on day 5 and discontinued on day 10 after SAH. Blood samples were drawn from the patients before, during and after prostacyclin/placebo infusion. Soluble biomarkers of endothelial cell activation (sE-selectin, sVE-cadherin) and damage (sTM), glycocalyx damage (syndecan-1) and sympathoadrenal activation (adrenaline, noradrenaline), were measured by ELISA. Ninety patients were randomized. Prostacyclin infusion influenced neither biomarkers of sympathoadrenal activation, endothelial activation and damage nor biomarkers of endothelial glycocalyx breakdown. We did not find any effects on markers of sympathoadrenal activation, endothelial damage and activation, or glycocalyx degradation of delayed onset prostacyclin infusion compared to placebo. Further trials investigating early onset endothelial repair using prostacyclin are warranted.

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.

A novel concept of pneumatic pump in the outpatient management of mixed leg ulceration: a pilot study

Mixed leg ulcer is a challenge in vascular diseases because both arterial and venous systems of the lower extremities are involved in the wound pathogenesis. Management is very difficult because the coexistence of the two conditions sometimes prevent to use compression bandaging, which is the cornerstone of venous leg ulcer treatment. It has been recently developed the so called gradient pump (GP), a novel device which permits to intermittently stop the flow in the femoral vein with a pneumatic cuff placed on the thigh. Subsequent release of the femoral vein compression determines a dramatic aspiration of the blood up-ward the heart, with synchronous and measured improved perfusion of the distal limb. We applied GP at 4 consecutive cases of multiple mixed painful ulcerations of the foot and leg scheduled for below knee and/or foot amputations. In all cases measure of pain by visual analogue scale significantly decreased; GP in most cases together intravenous infusion of synthetic prostacyclin led to improvement and/or minimal amputation. Therefore such a management can be done on outpatient bases, allowing a considerable lowering of health costs. We conclude that GP could be a valuable tool in the arsenal of mixed leg ulcer clinical assessment.

Endothelial Dysfunction in Resuscitated Cardiac Arrest (ENDO-RCA): safety and efficacy of low-dose prostacyclin administration and blood pressure target in addition to standard therapy, as compared to standard therapy alone, in post-cardiac arrest syndrome patients: study protocol for a randomized controlled trial.

BackgroundMorbidity and mortality following initial survival of cardiac arrest remain high despite great efforts to improve resuscitation techniques and post-resuscitation care, in part due to the ischemia-reperfusion injury secondary to the restoration of the blood circulation. Patients resuscitated from cardiac arrest display evidence of endothelial injury and coagulopathy (hypocoagulability, hyperfibrinolysis), which in associated with poor outcome. Recent randomized controlled trials have revealed that treatment with infusion of prostacyclin reduces endothelial damage after major surgery and AMI. Thus, a study is pertinent to investigate if prostacyclin infusion as a therapeutic intervention reduces endothelial damage without compromising, or even improving, the hemostatic competence in resuscitated cardiac arrest patients. Post-cardiac arrest patients frequently have a need for vasopressor therapy (catecholamines) to achieve the guideline-supported blood pressure goals. To evaluate a possible catecholamine interaction with the primary endpoints of this study, included patients will be randomized into two different blood pressure goals within guideline-recommended targets.Methods/designA randomized, placebo-controlled, double-blind investigator-initiated pilot trial in 40 out-of-hospital-cardiac-arrest (OHCA) patients will be conducted. Patients will be randomly assigned to either the active treatment group (48 hours of active study drug (iloprost, 1 ng/kg/min) or to the control group [placebo (saline) infusion]. Target mean blood pressure levels will be allocated 1:1 to 65 mmHg or approximately 75 mmHg, which gives four different permutations, namely: (i) iloprost/65 mHg, (ii) iloprost/75 mmHg, (iii) placebo/65 mmHg, and (iv) placebo/75 mmHg. All randomized patients will be treated in accordance with state-of-the art therapy including targeted temperature management.The primary endpoint of this study is change in biomarkers indicative of endothelial activation and damage, [soluble thrombomodulin (sTM), sE-selectin, syndecan-1, soluble vascular endothelial growth factor (sVEGF), nucleosomes] and sympathoadrenal over activation (epinephrine/norepinephrine) from baseline to 48 hours post-randomization.The secondary endpoints of this trial will include: (1) the hemostatic profile [change in functional hemostatic blood test (thrombelastography (TEG) and whole blood platelet aggregometry (multiplate)) blood cell and endothelial cell-derived microparticles]; (2) feasibility of blood pressure target intervention (target 90 %); (3) interaction of primary endpoints and blood pressure target; (4) levels of neuron-specific enolase at 48 hours post-inclusion according to blood pressure targets.DiscussionThe ENDO-RCA study is a pilot study trial that investigates safety and efficacy of low-dose infusion of prostacyclin administration as compared to standard therapy in post-cardiac arrest syndrome patients.Trial registrationTrial registration at ClinicalTrials.gov (identifier NCT02685618) on 18 February 2016.

Severe pulmonary arterial hypertension: stratification of medical therapies, mechanical support, and lung transplantation.

Severe pulmonary hypertension is recognized by focusing on the clinical signs and tests that demonstrate decompensated right ventricular failure or, in the worst-case scenario, shock. An aggressive treatment regimen including a prostacyclin infusion is required for these patients. Once admitted to the hospital, or the ICU for decompensated right ventricular failure, the short- and long-term outcomes for PAH patients are poor. For those who are candidates, urgent lung transplantation, or extracorporeal membrane oxygenation (ECMO) as a bridge to lung transplantation may be rescue therapy.