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1.
J Crit Care ; 69: 153989, 2022 06.
Article in English | MEDLINE | ID: covidwho-1814662

ABSTRACT

PURPOSE: Acute lung injury associated with COVID-19 contributes significantly to its morbidity and mortality. Though invasive mechanical ventilation is sometimes necessary, the use of high flow nasal oxygen may avoid the need for mechanical ventilation in some patients. For patients approaching the limits of high flow nasal oxygen support, addition of inhaled pulmonary vasodilators is becoming more common but little is known about its effects. This is the first descriptive study of a cohort of patients receiving inhaled epoprostenol with high flow nasal oxygen for COVID-19. MATERIALS AND METHODS: We collected clinical data from the first fifty patients to receive inhaled epoprostenol while on high flow nasal oxygen at our institution. We compared the characteristics of patients who did and did not respond to epoprostenol addition. RESULTS: The 18 patients that did not stabilize or improve following initiation of inhaled epoprostenol had similar rates of invasive mechanical ventilation as those who improved or stabilized (50% vs 56%). Rates of mortality were not significantly different between the two groups (17% and 31%). CONCLUSIONS: In patients with COVID-19 induced hypoxemic respiratory failure, the use of inhaled epoprostenol with high flow nasal oxygen is feasible, but physiologic signs of response were not related to clinical outcomes.


Subject(s)
COVID-19 , Noninvasive Ventilation , Respiratory Insufficiency , COVID-19/drug therapy , Cannula , Epoprostenol/therapeutic use , Humans , Noninvasive Ventilation/adverse effects , Oxygen , Oxygen Inhalation Therapy , Respiratory Insufficiency/therapy
2.
Respir Med ; 193: 106744, 2022 03.
Article in English | MEDLINE | ID: covidwho-1740161

ABSTRACT

Oral treprostinil has been shown to improve exercise capacity and delay disease progression in patients with pulmonary arterial hypertension (PAH), but its effects on hemodynamics are not well-characterized. The FREEDOM-EV trial was a Phase III, international, placebo-controlled, double-blind, event-driven study in 690 participants with PAH who were taking a single oral PAH therapy. FREEDOM-EV demonstrated a significantly reduced risk for clinical worsening with oral treprostinil taken three times daily and did not uncover new safety signals in PAH patients. Sixty-one participants in the FREEDOM-EV trial volunteered for a hemodynamics sub-study. Pulmonary artery compliance (PAC), a ratio of stroke volume to pulmonary pulse pressure, significantly increased from Baseline to Week 24 in the oral treprostinil group compared with the placebo group (geometric mean 26.4% active vs. -6.0% placebo; ANCOVA p=0.007). There was a significant increase in cardiac output in the oral treprostinil group compared to the placebo group (geometric mean 11.3% active vs. -6.4% placebo; ANCOVA p=0.005) and a corresponding significant reduction in pulmonary vascular resistance (PVR) (geometric mean -21.5 active vs. -1.8% placebo; ANCOVA p=0.02) from Baseline to Week 24. These data suggest that increased compliance contributes to the physiological mechanism by which oral treprostinil improves exercise capacity and delays clinical worsening for patients with PAH.


Subject(s)
Pulmonary Arterial Hypertension , Antihypertensive Agents , Epoprostenol/analogs & derivatives , Epoprostenol/therapeutic use , Humans , Pulmonary Arterial Hypertension/drug therapy , Treatment Outcome , Vascular Resistance
3.
Hosp Pract (1995) ; 50(2): 118-123, 2022 Apr.
Article in English | MEDLINE | ID: covidwho-1713461

ABSTRACT

OBJECTIVES: Patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) frequently present with a febrile illness that may progress to pneumonia and hypoxic respiratory failure. Aerosolized epoprostenol (aEPO) has been evaluated in patients with acute respiratory distress syndrome and refractory hypoxemia. A paucity of literature has assessed the impact of aEPO in patients with SARS-CoV-2 receiving oxygen support with high flow nasal cannula (HFNC). The objective of this study was to evaluate whether aEPO added to HFNC prevents intubation and/or prolong time to intubation compared to controls only treated with HFNC, guided by oxygen saturation goals. METHODS: This was a single-center, retrospective study of adult patients infected with coronavirus 2019 (COVID-19) and admitted to the medical intensive care unit. A total of 60 patients were included. Thirty patients were included in the treatment, and 30 in the control group, respectively. Among patients included in the treatment group, response to therapy was assessed. The need for mechanical ventilation and hospital mortality between responders vs. non-responders was evaluated. RESULTS: The primary outcome of mechanical ventilation was not statistically different between groups. Time from HFNC initiation to intubation was significantly prolonged in the treatment group compared to the control group (5.7 days vs. 2.3 days, P = 0.001). There was no statistically significant difference between groups in mortality or length of stay. Patients deemed responders to aEPO had a lower rate of mechanical ventilation (50% vs 88%, P = 0.025) and mortality (21% vs 63%, P = 0.024), compared with non-responders. CONCLUSION: The utilization of aEPO in COVID-19 patients treated with HFNC is not associated with a reduction in the rate of mechanical ventilation. Nevertheless, the application of this strategy may prolong the time to invasive mechanical ventilation, without affecting other clinical outcomes.


Subject(s)
COVID-19 , Noninvasive Ventilation , Respiratory Insufficiency , Adult , Epoprostenol/therapeutic use , Humans , Hypoxia/drug therapy , Oxygen Inhalation Therapy , Respiratory Insufficiency/therapy , Retrospective Studies , SARS-CoV-2
4.
J Crit Care ; 69: 154010, 2022 06.
Article in English | MEDLINE | ID: covidwho-1693300

ABSTRACT

BACKGROUND: In 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. METHODS: Post-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. RESULTS: Eighty 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. CONCLUSIONS: Prostacyclin 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.


Subject(s)
COVID-19 , Epoprostenol , Adult , Biomarkers , Endothelium, Vascular , Epoprostenol/pharmacology , Epoprostenol/therapeutic use , Humans , Pilot Projects , Respiration, Artificial , SARS-CoV-2 , Syndecan-1
6.
J Intensive Care Med ; 36(3): 327-333, 2021 Mar.
Article in English | MEDLINE | ID: covidwho-945132

ABSTRACT

BACKGROUND: Inhaled pulmonary vasodilators are used as adjunctive therapies for the treatment of refractory hypoxemia. Available evidence suggest they improve oxygenation in a subset of patients without changing long-term trajectory. Given the differences in respiratory failure due to COVID-19 and "traditional" ARDS, we sought to identify their physiologic impact. METHODS: This is a retrospective observational study of patients mechanically ventilated for COVID-19, from the ICUs of 2 tertiary care centers, who received inhaled epoprostenol (iEpo) for the management of hypoxemia. The primary outcome is change in PaO2/FiO2. Additionally, we measured several patient level features to predict iEpo responsiveness (or lack thereof). RESULTS: Eighty patients with laboratory confirmed SARS-CoV2 received iEpo while mechanically ventilated and had PaO2/FiO2 measured before and after. The median PaO2/FiO2 prior to receiving iEpo was 92 mmHg and interquartile range (74 - 122). The median change in PaO2/FiO2 was 9 mmHg (-9 - 37) corresponding to a 10% improvement (-8 - 41). Fifty-percent (40 / 80) met our a priori definition of a clinically significant improvement in PaO2/FiO2 (increase in 10% from the baseline value). Prone position and lower PaO2/FiO2 when iEpo was started predicted a more robust response, which held after multivariate adjustment. For proned individuals, improvement in PaO2/FiO2 was 14 mmHg (-6 to 45) vs. 3 mmHg (-11 - 20), p = 0.04 for supine individuals; for those with severe ARDS (PaO2/FiO2 < 100, n = 49) the median improvement was 16 mmHg (-2 - 46). CONCLUSION: Fifty percent of patients have a clinically significant improvement in PaO2/FiO2 after the initiation of iEpo. This suggests it is worth trying as a rescue therapy; although generally the benefit was modest with a wide variability. Those who were prone and had lower PaO2/FiO2 were more likely to respond.


Subject(s)
COVID-19/therapy , Epoprostenol/therapeutic use , Hypoxia/therapy , Respiration, Artificial , Respiratory Insufficiency/therapy , Vasodilator Agents/therapeutic use , Administration, Inhalation , Aged , Female , Humans , Hypoxia/metabolism , Male , Middle Aged , Oxygen/metabolism , Partial Pressure , Patient Positioning , Prone Position , Retrospective Studies , SARS-CoV-2 , Severity of Illness Index , Tertiary Care Centers , Treatment Outcome
7.
Nat Rev Cardiol ; 18(3): 194-209, 2021 03.
Article in English | MEDLINE | ID: covidwho-936141

ABSTRACT

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


Subject(s)
Blood Coagulation Disorders/blood , Blood Platelet Disorders/blood , COVID-19/blood , Endothelium, Vascular/physiopathology , Inflammation/blood , Thrombosis/blood , Administration, Inhalation , Anticoagulants/therapeutic use , Blood Coagulation Disorders/drug therapy , Blood Coagulation Disorders/etiology , Blood Coagulation Disorders/physiopathology , Blood Platelet Disorders/drug therapy , Blood Platelet Disorders/etiology , Blood Platelet Disorders/physiopathology , COVID-19/complications , COVID-19/drug therapy , COVID-19/physiopathology , Endothelium-Dependent Relaxing Factors/therapeutic use , Epoprostenol/therapeutic use , Heart Disease Risk Factors , Humans , Iloprost/therapeutic use , Inflammation/etiology , Inflammation/physiopathology , Nitric Oxide/therapeutic use , Platelet Aggregation Inhibitors/therapeutic use , SARS-CoV-2 , Systemic Inflammatory Response Syndrome/blood , Systemic Inflammatory Response Syndrome/drug therapy , Systemic Inflammatory Response Syndrome/physiopathology , Thrombosis/etiology , Thrombosis/immunology , Thrombotic Microangiopathies/blood , Thrombotic Microangiopathies/drug therapy , Thrombotic Microangiopathies/etiology , Thrombotic Microangiopathies/physiopathology , Vascular Diseases/blood , Vascular Diseases/drug therapy , Vascular Diseases/etiology , Vascular Diseases/physiopathology , Vasodilator Agents/therapeutic use , Venous Thromboembolism/blood , Venous Thromboembolism/drug therapy , Venous Thromboembolism/etiology , Venous Thromboembolism/physiopathology
8.
Drug Dev Res ; 82(2): 217-229, 2021 04.
Article in English | MEDLINE | ID: covidwho-798845

ABSTRACT

Coronavirus disease 2019 (COVID 19) was first identified in Wuhan, China near the end of 2019. To date, COVID-19 had spread to almost 235 countries and territories due to its highly infectious nature. Moreover, there is no vaccine or Food and Drug Administration (FDA)-approved drug. More time is needed to establish one of them. Consequently, the drug repurposing approach seems to be the most attractive and quick solution to accommodate this crisis. In this regard, we performed molecular docking-based virtual screening of antiplatelet FDA-approved drugs on the key two viral target proteins: main protease (Mpro ) and spike glycoprotein (S) as potential inhibitor candidates for COVID-19. In the present study, 15 antiplatelet FDA-approved drugs were investigated against the concerned targets using the Molecular Docking Server. Our study revealed that only cilostazol has the most favorable binding interaction on Mpro (PDB ID: 6LU7) and cilostazol, iloprost, epoprostenol, prasugrel, and icosapent ethyl have a higher binding affinity on spike glycoprotein (S) (PDB ID: 6VYB) compared with recent anti-CoVID-19. Therefore, cilostazol is a promising FDA drug against COVID-19 by inhibiting both Mpro and S protein. The insights gained in this study may be useful for quick approach against COVID-19 in the future.


Subject(s)
COVID-19/drug therapy , Coronavirus 3C Proteases/metabolism , Platelet Aggregation Inhibitors/metabolism , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Cilostazol/metabolism , Cilostazol/therapeutic use , Drug Approval , Drug Evaluation, Preclinical , Drug Repositioning , Eicosapentaenoic Acid/analogs & derivatives , Eicosapentaenoic Acid/metabolism , Eicosapentaenoic Acid/therapeutic use , Epoprostenol/metabolism , Epoprostenol/therapeutic use , Humans , Iloprost/metabolism , Iloprost/therapeutic use , Molecular Docking Simulation , Platelet Aggregation Inhibitors/therapeutic use , Prasugrel Hydrochloride/metabolism , Prasugrel Hydrochloride/therapeutic use , United States , United States Food and Drug Administration
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