Inhaled Prostacyclin Improves Oxygenation in Patients with COVID-19-induced Acute Respiratory Distress Syndrome

Background. Acute Respiratory Distress Syndrome (ARDS) results in significant hypoxia, and ARDS is the central pathology of COVID-19. Inhaled prostacyclin has been proposed as a therapy for ARDS, but data regarding its role in this syndrome are unavailable. Therefore, we investigated whether inhaled prostacyclin would affect the oxygenation and survival of patients suffering from ARDS. Methods. We performed a prospective randomized controlled single-blind multicenter trial across Germany. The trial was conducted from March 2019 with final follow-up on 12 th of August 2021. Patients with moderate to severe ARDS were included and randomized to receive either inhaled prostacyclin (3 times/day for 5 days) or sodium chloride. The primary outcome was the oxygenation index in the intervention and control groups on Day 5 of therapy. Secondary outcomes were mortality, secondary organ failure, disease severity and adverse events. Findings. Of 707 patients approached 150 patients were randomized to receive inhaled prostacyclin (n=73) or sodium chloride (n=77). Data from 144 patients were analyzed. The baseline oxygenation index did not differ between groups. The primary analysis of the study was negative, and prostacyclin improved oxygenation by 20 mmHg more than NaCl (p=0.17). Oxygenation was significantly improved in patients with ARDS who were COVID-19-positive (34 mmHg, p=0.04). Mortality did not differ between groups. Secondary organ failure and adverse events were similar in the intervention and control groups. Interpretation. Although the primary result of our study was negative, our data suggest that inhaled prostacyclin might be a more beneficial treatment than standard care for patients with ARDS.

Inhaled prostacyclin analogues in COVID-19 associated acute respiratory distress syndrome: scientific rationale

Background COVID-19 associated acute respiratory distress syndrome (CARDS) is a severe form of SARS CoV-2 infection and affects about 15–30% of hospitalized patients with a high mortality rate. Growing research and data suggest several available drugs with appropriate pharmacological effects to treat COVID-19. Main body Prostacyclin analogues are regiments for pulmonary artery hypertension. Prostacyclin analogues are expected to be beneficial in treating CARDS based on at least four rationales: (1) inhaled prostacyclin analogues improve oxygenation, V/Q mismatch, and act as an ARDS therapy alternative; (2) it alleviates direct SARS-CoV-2-related coagulopathy; (3) increases nitric oxide production; and (4) possible anti-inflammatory effect. Prostacyclin analogues are available in oral, intravenous, and inhaled forms. The inhaled form has the advantage over other forms, such as parenteral administration risks. Previously, a meta-analysis demonstrated the beneficial effects of inhaled prostaglandins for ARDS treatment, such as improved PaO2/FiO2 and PaO2 along with reduced pulmonary artery pressure. Currently, two ongoing randomized controlled trials are evaluating inhaled epoprostenol (VPCOVID [NCT04452669]) and iloprost (ILOCOVID [NCT04445246]) for severe COVID-19 patients. Conclusions Inhaled prostacyclin could be considered in patients with refractory, life-threatening hypoxia despite standard management.

Characterization of cough evoked by inhaled treprostinil and treprostinil palmitil

Cough is induced by inhaled prostacyclin analogs including treprostinil (TRE), and, at higher doses, treprostinil palmitil (TP), a prodrug of TRE. In this report, we have investigated mechanisms involved with TRE- and TP-induced cough, using a dry powder formulation of TP (TPIP) to supplement previous data obtained with an aqueous suspension formulation of TP (TPIS).Experiments in guinea pigs and rats investigated the prostanoid receptor subtype producing cough and whether it involved activation of sensory nerves in the airways and vasculature. Experiments involved treatment with prostanoid, tachykinin and bradykinin receptor antagonists, a cyclooxygenase inhibitor and TRE administration to the isolated larynx or intravenously.In guinea pigs, cough with inhaled TRE (1.23 µg·kg−1) was not observed with an equivalent dose of TPIP and required higher inhaled doses (12.8 and 35.8 µg·kg) to induce cough. TRE cough was blocked with IP and tachykinin NK1 receptor antagonists but not with EP1, EP2, EP3, DP1 or bradykinin B2 antagonists or a cyclooxygenase inhibitor. TRE administered to the isolated larynx or intravenously in rats produced no apnea or swallowing, whereas citric acid, capsaicin and hypertonic saline had significant effects.The mechanisms inducing cough with inhaled TRE likely involves the activation of prostanoid IP receptors on jugular C-fibers in the tracheobronchial airways. Cough induced by inhaled dry powder and nebulised formulations of TP occurs at higher inhaled doses than TRE, presumably due to the slow, sustained release of TRE from the prodrug resulting in lower concentrations of TRE at the airway sensory nerves.

Clinical efficacy and safety of nebulized prostacyclin in patients with sARs-CoV-2 (prospective comparative study)

Aim. In this study we evaluated clinical effectiveness and safety of nebulized prostacyclin in patients with Novel Coronavirus Disease (SARS-CoV-2). Materials and methods: We have included 44 male patients with moderate PCR confirmed SARS-CoV-2 infection in this study. Control group consisted of 23 patients treated with nebulized prostacyclin (PGI2). besides standard therapy. We compared intensiveness and duration of infectious intoxication syndrome, duration of fever, cough as well as SpO2 level, complete blood count and chemokine status values. Results: Statistically significant difference in duration of fever, cough, intensiveness and duration of infectious intoxication syndrome were observed. Lymphocyte and platelet counts were significantly higher in control group We have also noticed significantly lower level of proinflammatory mediators and C4-complement component in control group. Only 1 adverse effect associated with inhaled prostacyclin was reported. Conclusion. Nebulized prostacyclin showed therapeutic efficacy and good safety profile in adults with moderate COVID-19.

P31 Compatibility of sildenafil citrate with noradrenaline and vasopressin during simulated y-site administration

AimOff-label use of IV sildenafil (Revatio) is one of the limited treatment options available in the treatment of Pulmonary Hypertension in the paediatric and neonatal population. The lack of compatibility data on the co-administration of IV sildenafil with other drugs in critical care means a dedicated line is required for sildenafil. However, in critically unwell patients multiple drug infusions are commonly administered and the dedication of an IV line for sildenafil could be problematic and can further increase the risks of adverse events.1,2 Our Lady’s Children’s Hospital Crumlin in Dublin Ireland, identified the following five drugs as critical and commonly encountered in PICU; Adrenaline, Noradrenaline, Vasopressin, Milrinone and Heparin. The aim of this study is to determine the physical and chemical compatibility of Noradrenaline and Vasopressin in combination with Sildenafil.MethodTo simulate Y-site conditions the drugs were mixed in a 1:1 ratio as previously demonstrated by Allen et al.3 Clear glass tubes as specified by the EP, were used to allow for the investigation of compatibility at specific time-points across a 24 hour period at room temperature. Drugs were prepared in accordance with clinical practice; Noradrenaline 60 micrograms/ml, vasopressin 0.4 units/ml and sildenafil 800 micrograms/ml. Different diluents: NaCl 0.9% w/v, Glucose 5% w/v and Glucose 10% w/v were examined. Chemical compatibility was assessed using HPLC and physical by pH determination and visual inspection of contents. Drugs were deemed compatible if concentrations of both remained between 90% and 110% of the original concentration3 and if no signs of physical incompatibility was noted (i.e. pH change, haze or cloudiness).ResultsNo physical incompatibility was noted between the compounds with stable pH and no visual changes. Concentrations of vasopressin, noradrenaline and sildenafil were all within concentration limits indicating chemical compatibility.ConclusionThe limited and incomplete data presented in the literature for the compatibility of drugs administered via Y-site in combination with sildenafil, makes studies such as this one invaluable to clinicians. The overall aim of this work is to provide a complete compatibility chart of all five drugs identified as critical in combination with Sildenafil at RT and at 37°C. This preliminary data provides a starting point in the investigation of the compatibility of Sildenafil in combination with commonly used ICU drug infusions.ReferencesFender RA, Hasselman TE, Wang Y, Harthan AA. Evaluation of the tolerability of intermittent intravenous sildenafil in paediatric patients with pulmonary hypertension. JPPT2016;21(5):419–25.Kelly LK, Porta NFM, Goodman DM, Carroll CL, Steinhorn RH. Inhaled prostacyclin for term infants with persistent pulmonary hypertension refractory to inhaled nitric oxide. JPeds2002;141(6):830–2.Allen LV, Jr., Levinson RS, Phisutsinthop D. Compatibility of various admixtures with secondary additives at Y-injection sites of intravenous administration sets. Am J Hosp Pharm1977;34(9):939–43.