SCCM Resource Library-09-Evaluation of Aerosolized Epoprostenol in COVID-19 ARDS Patients

Video Transcription

Hi, everyone, and thank you for joining this presentation. My name is Mahmoud Ammar. I'm a critical care pharmacist at the Yale New Haven Hospital.  And today, I'll be sharing with you the results of our study, which is titled Evaluation of Aerosolized Eoprostenil in COVID-19 Patients.  To start with, I want to acknowledge the rest of my research team that worked on this project. I have no actual or potential conflict of interest in relation to the content of this  presentation. As we're all aware, COVID-19 is a multisystem thromboinflammatory disorder that leads to  significant morbidity and mortality, particularly in the cardiorespiratory system. End-stage COVID-19 is characterized by severe acute respiratory distress syndrome, or ARDS,  as well as disseminated thrombosis, with venous thromboembolism, arterial thrombosis, and thrombotic microangiopathy being frequently reported in autopsy of these patients.  To date, there are no well-established treatments for COVID-19, and respiratory support remains the cornerstone of care for these patients.  Prostacyclin and nautric oxide have a potent vasodilator antiplatelet effect and are currently being utilized as adjunctive therapies in patients with COVID-19 ARDS.  However, the role of aerosolized eoprostenil in the management of COVID-19 patient has not been adequately evaluated.  This prompted us to do this study to evaluate the use of aerosolized eoprostenil in the management of COVID-19 with a primary objective of evaluating the effect of eoprostenil on  oxygenation parameters, specifically improvement in PF ratios in these patients. And our secondary objectives were to evaluate the effect of eoprostenil on arterial to  end-tidal CO2 gradient, and also to evaluate the effect of eoprostenil on coagulation factors, such as D-dimer and fibrinogen levels.  We also wanted to evaluate the effect of eoprostenil on mechanical ventilation free days, intensive care unit length of stay, and 28-day mortality.  In terms of safety of eoprostenil, we evaluated the incidence of hypotension, significant bleeding, and thrombocytopenia.  In this study, hypotension was assessed based on whether patients received vasopressor support or not.  In patients receiving vasopressors, hypotension was defined as an increase in pressure requirements by 20%.  Bleeding was assessed based on significant drop in hemoglobin by 2 gram per deciliter in a 24-hour period, and the need for blood transfusion.  This was a single-center, retrospective, propensity-matched case-control study that included adult patients  with positive COVID-19 PCR tests and who were mechanically ventilated and with ARDS. ARDS in this study was defined based on the PROLINC criteria, including having a PF ratio  less than 300 mmHg, and with hypercapnic respiratory failure based on elevated partial pressure of carbon dioxide more than 45 mmHg, and respiratory acidosis based on pH values from  ABG labs. In this study, we excluded patients who were at high risk for bleeding, such as patients  with previous intracranial hemorrhage, history of clinically significant bleeding requiring transfusion, and severe thrombocytopenia.  We also excluded patients who were receiving therapeutic anticoagulation or antiplatelet therapy or receiving other endothelial receptor antagonists and therapies that are listed  on this slide. As you can see, we started with a large cohort, but after assessing for inclusion and exclusion  criteria, we identified 24 patients who are eligible to be in the euprostonal cohort and 39 patients who are eligible to be in the control group.  However, these patients demonstrated significant difference in baseline characteristics, with respiratory parameters, including PF ratio, and high risk of morbidities being worse in  the euprostonal group compared to the control group. So then we conducted a propensity score matching based on Rothman index and baseline PF ratio,  and we identified 19 patients for both cohorts, and we proceeded in evaluating our outcomes. This slide shows the patient's baseline characteristics.  In these matched groups, no significant differences were observed in baseline characteristics, including baseline comorbidities.  There were also no difference in baseline severity of illness, including Rothman index at hospital admission and SOFA score at ICU admission.  There was no difference in oxygenation parameters at baseline, including PF ratio, AA gradient, and dead space.  And there was no difference in coagulation parameters, which included D-dimer, fibrinogen levels, and platelet count at baseline.  This slide shows the results of the respiratory parameters in patients who received euprostonal in comparison to the control group.  Figure A, B, and C shows the respiratory baseline parameters, including PF ratio, dead space, and AA gradient, which, as you can see, were not significantly different between  the euprostonal treated and the control group. Figure D depicts the PF ratio findings. Unexpectedly, despite both groups showing improvement in PF ratio, the euprostonal treated  group was associated with significantly lower PF ratios at day 3, 5, and 6. With regards to the AA gradient, which is shown here in figure E, there was significant  increases in the AA gradient at days 3, 4, and 6 after initiation of euprostonal therapy compared to the control.  Regarding to the dead space finding, which is shown here in figure F, there was higher dead space reported in the euprostonal group compared to the control.  These findings were not what we expected, and it might be due to the treated group being a sicker cohort despite the matching.  Or at a pathophysiological level, might reflect vasodilation of hypoxic constricted arteries  at unventilated airways, leading to increased ventilation perfusion mismatch, which would have resulted in this worsening in PF ratios.  Another possibility for the deteriorated respiratory status might be the interstitial edema from the vasodilatory effect of euprostonal.  Also, this acute vasodilation could have potentially induced ischemic reperfusion damage. Mortality was assessed by the Kaplan-Meier survival analysis using the log-rank test,  which is depicted in this figure. Despite worsening of oxygenation parameters in the euprostonal group, as presented in  the previous slide, the Kaplan-Meier assessment of survival revealed unexpected survival benefit.  The mass control group showed a steady and constant patient loss over a 28-day period, while the euprostonal treated patients had no mortality in the first 10 days after the  initiation of treatment. At later time points, days 11 to day 24, there was a progressive decline in the survival  of the euprostonal group, ultimately leading to non-significant differences in mortality rate by day 24.  This led us to also examine the larger unmatched cohort, which is reported in figure H on this  slide, which showed similar findings to the matched cohort, specifically that the survival difference in the first 10 days remained. This slide shows the thrombus formation data.  In the first 10 days of treatment, fibrinogen, platelet count, and D-dimer were not significantly different at baseline.  Fibrinogen, which is a clotting factor as well as an acute phase reactant, decreased in both the euprostonal and control group, which is shown here in figure D, while platelet  counts increased in the control group but remained unchanged in the euprostonal cohort, which is shown here in figure E.  However, the D-dimer levels increased in the control group and decreased in the euprostonal group, which is depicted here in figure F.  We also assessed fibrinogen trends over time using linear regression, which showed that the euprostonal groups had a significant negative slope compared to the control group, which  increased. Looking at this data, it could be hypothesized that the D-dimer, which is the fibrinogen  degradation product that is present in blood after a blood clot is degraded, was stable,  reflecting that thrombosis was stable in patients who received euprostonal treatment compared to the control patients who did not receive euprostonal therapy.  We also evaluated other outcomes in this cohort, and we identified no significant difference in mechanical ventilation free days.  Also, there was no significant difference in safety outcomes evaluated, which included hypertension, significant bleeding, and thrombocytopenia.  However, patients who received euprostonal therapy had a longer ICU and hospital length of stay. This study has several limitations.  We acknowledge that our study is a small study and from a single center, and thus a large randomized controlled trial is required to gauge the true mortality benefit reported  in this study. It can also be argued that the mortality differences noted in this study may still arise from selection bias.  However, we attempted to account for severity of illness and ARDS at baseline in the propensity score matching design of this study.  Even though propensity score matching was used, it might not have accounted for all baseline characteristics, which is a limitation for the design of this study.  Finally, the management of ARDS in COVID-19 patients remained under evaluation, and thus it's not clear whether the ARDS guideline recommendations apply to COVID-19 patients.  However, in this analysis, other therapies for ARDS, as well as strict exclusion criteria, were used to ensure both cohorts were managed similarly.  And this data is not shown in this presentation, but it was collected at baseline. As a conclusion, along with COVID-19 associated coagulopathy, platelet dysfunction with platelet  hyperactivation is increasingly being recognized as an underlying cause for the increased thrombosis observed with COVID-19 patients.  In this small sample, inhaled prostacyclin therapy paradoxically led to worse respiratory effects but improved short-term survival with improved D-dimer.  Finally, this study could potentially advocate to consider antiplatelet agents for the prophylaxis  and treatment of severely ill COVID-19 patients, and definitely larger randomized controlled trials are needed to further explore these findings.  By this, I'll thank you for taking the time to attend this presentation, and I'll be happy to answer any of your questions.

Video Summary

In this presentation, Mahmoud Ammar, a critical care pharmacist at Yale New Haven Hospital, shares the results of a study titled "Evaluation of Aerosolized Eoprostenil in COVID-19 Patients." The study aims to evaluate the use of aerosolized eoprostenil in the management of COVID-19 patients, specifically looking at its effect on oxygenation parameters, coagulation factors, mechanical ventilation, length of stay, and mortality. The study included 24 patients in the eoprostenil group and 39 patients in the control group, with matching done to analyze the outcomes. Surprisingly, the eoprostenil group showed worse respiratory effects, but had improved short-term survival and decreased D-dimer levels. The study suggests that antiplatelet agents may be considered for severely ill COVID-19 patients but further research is needed.

Asset Subtitle

Pulmonary, Crisis Management, 2021

Asset Caption

The Society of Critical Care Medicine's Critical Care Congress features internationally renowned faculty and content sessions highlighting the most up-to-date, evidence-based developments in critical care medicine. This is a presentation from the 2021 Critical Care Congress held virtually from January 31-February 12, 2021.

Mahmoud A. Ammar, BCCCP, BCPS, PharmD

Introduction/Hypothesis: ARDS contributes to high mortality and morbidity observed with coronavirus disease 2019 (COVID-19). Epoprostenol has antithrombotic, antiproliferative, and vasodilatory properties and improves respiratory parameters in ARDS. The role of aerosolized epoprostenol (aEPO) in COVID-19 has not been evaluated. We hypothesized that aEPO may improve oxygenation in intubated COVID-19 patients.

Methods: We performed a single-center, retrospective, propensity-score matched cohort study. A medical chart review was conducted for COVID-19 ARDS adult patients admitted between March 1, 2020 and May 1, 2020. Patients receiving aEPO (0.05 mcg/kg/minute) versus patients not receiving aEPO were matched for Rothman index and baseline PaO2:FiO2 (PF) ratios, and evaluated for effect of aEPO on PF ratio, gradient between arterial to end-tidal CO2, and dead space (primary endpoints). Secondary endpoints evaluated included in-hospital mortality, mechanical ventilation-free days, and ICU and hospital length of stay. Safety endpoints evaluated included incidence of hypotension, significant bleeding, thrombocytopenia, and rebound hypoxemia.

Results: Nineteen patients treated with aEPO were compared to 19 propensity-matched controls. Baseline characteristics were well matched. Management of ARDS was similar between groups. The mean Â± SD duration of aEPO treatment was 5 Â± 2.8 days. There were no significant differences in PF ratios between aEPO cohort and non-aEPO cohort at 3 hours (125 Â± 56 vs 115 Â± 40 mmHg), 6 hours (124 Â± 41 vs 147 Â± 73 mmHg), 12 hours (112 Â± 39 vs 163 Â± 62 mmHg), 24 hours (114 Â± 33 vs 176 Â± 64 mmHg), and 48 hours (150 Â± 54 vs 212 Â± 84 mmHg), although there was a trend toward higher PF ratios for the control group. There were no significant differences in gradient between arterial to end-tidal CO2 and dead space between cohorts. There were significantly more deaths in the control group compared to aEPO by day 10 (21% vs 0, p<0.05), though there was no difference in 28-day mortality (41% vs 48%, p=0.35). There were no significant differences in other secondary and safety end points.

Conclusions: In this small case-control study, aEPO did not demonstrate better efficacy or safety compared to not receiving aEPO. Large randomized control trials are needed to confirm early survival benefit noted with aEPO.

Meta Tag

Content Type Presentation

Knowledge Area Pulmonary

Knowledge Area Crisis Management

Knowledge Level Advanced

Membership Level Select

Tag COVID-19

Tag Acute Respiratory Distress Syndrome ARDS

Year 2021

Keywords

aerosolized eoprostenil

oxygenation parameters

coagulation factors

mechanical ventilation

antiplatelet agents

	Society of Critical Care Medicine 500 Midway Drive Mount Prospect, IL 60056 USA Phone: +1 847 827-6888 Fax: +1 847 439-7226 Email: support@sccm.org	Contact Us About SCCM Newsroom Advertising & Sponsorship DONATE	MySCCM LearnICU Patients & Families Surviving Sepsis Campaign Critical Care Societies Collaborative	GET OUR NEWSLETTER
© Society of Critical Care Medicine. All rights reserved. \| Privacy Statement \| Terms & Conditions The Society of Critical Care Medicine, SCCM, and Critical Care Congress are registered trademarks of the Society of Critical Care Medicine.