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Sildenafil for the Treatment of Patients With COVID-19 and Perfusion Mismatch on Subtraction Computed Tomography Angiography: A Pilot, Placebo-Controlled Randomised Trial

40 Pages Posted: 15 Jul 2021

See all articles by Mario G. Santamarina

Mario G. Santamarina

Hospital Naval Almirante Nef - Radiology Department

Ignacio Beddings

Clinica Bupa Santiago - Radiology Department

Felipe Martinez Lomakin

Hospital Naval Almirante Nef - Intensive Care Unit

Dominique Boisier Riscal

Hospital Naval Almirante Nef - Intensive Care Unit

Mónica Gutiérrez Claveria

Hospital Naval Almirante Nef - Respiratory Department

Jaime Vidal Marambio

Hospital Naval Almirante Nef - Intensive Care Unit

Nicole Retamal Báez

Hospital Naval Almirante Nef - Intensive Care Unit

Cristian Pávez Novoa

Hospital Naval Almirante Nef - Intensive Care Unit

César Reyes Allende

Hospital Naval Almirante Nef - Intensive Care Unit

Paulina Ferreira Perey

Hospital Naval Almirante Nef - General Internal Medicine Department

Miguel Gutiérrez Torres

Hospital Naval Almirante Nef - General Internal Medicine Department

Camila Villalobos Mazza

Hospital Naval Almirante Nef - Infectious Disease Department

Constanza Vergara Sagredo

Hospital Naval Almirante Nef - Intensive Care Unit

Sebastian Ahumada Bermejo

Hospital Naval Almirante Nef - Respiratory Department

Eduardo Labarca Mellado

Hospital Naval Almirante Nef - Intensive Care Unit

Elizabeth Barthel Munchmeyer

Hospital Naval Almirante Nef - Infectious Disease Department

Solange Marchant Ramos

Hospital Naval Almirante Nef - Hospital Pharmacy Department

Mariano Volpacchio

Centro de Diagnóstico Dr. Enrique Rossi - Radiology Department

Jorge Vega Stieb

Hospital Naval Almirante Nef - General Internal Medicine Department

More...

Abstract

Background: Severe gas exchange impairment can develop even in initial stages of COVID-19 pneumonia. SARS-CoV-2 seems to affect the regulation of pulmonary perfusion, through a renin-angiotensin system imbalance that occurs as a result of the virus binding to ACE2. Hypoperfusion to areas of well-aerated lung parenchyma results in a ventilation-perfusion mismatch that can be characterized using subtraction computed tomography angiography (sCTA). We aimed to investigate the potential efficacy and safety of oral sildenafil in the treatment of inpatients with COVID-19 that showed perfusion abnormalities in sCTA.

Methods: This triple-blind, single-centre, placebo-controlled trial, was done at Hospital Naval Almirante Nef, Chile. We enrolled adult patients (>18 years of age) with clinically diagnosed, highly probable or confirmed COVID-19 infection, that were admitted for inpatient treatment, and with a sCTA carried out within 24 hours of admission that showed perfusion abnormalities in areas of well-aerated lung parenchyma. Patients were randomly assigned (1:1) to receive sildenafil (25 mg orally three times a day for seven days) or placebo. The primary endpoint was the change in the ratio between arterial oxygen partial pressure and fractional inspired oxygen (PaO2/FiO2 ratio), and a co-primary endpoint was the change in alveolar-arterial oxygen gradient (A-a gradient), both of which were calculated 1 hour after administration of the intervention on the first day, and on a daily basis during follow-up, using samples from an arterial line in all patients, and analysed using a two-way repeated-measures analysis of variance (ANOVA). Secondary endpoints including intensive care unit admission, the requirement of non-invasive mechanical ventilation or requirement of high-flow nasal cannula, initiation of mechanical ventilation and mortality rates were evaluated using survival analysis with the Kaplan-Meier method and log-rank statistic. The trial is now done. This trial is registered with ClinicalTrials.gov, NCT04489446.

Findings: Between August 20, 2020 and March 31, 2021, we recruited 20 patients per group. No statistically significant differences in mean PaO2/FiO2 ratios (repeated measures ANOVA p=0·67) and A-a gradients (repeated measures ANOVA p=0·69) were found between study groups. Invasive mechanical ventilation had to be initiated in four patients, all in the placebo arm, showing a statistically significant difference with the sildenafil arm (logrank p=0·04). Patients allocated to the sildenafil arm also showed a significantly shorter median length of stay in the hospital when compared with the placebo group (9 IQR 7-12 days vs 12 IQR 9-21 days, p=0·04).

Interpretation: Sildenafil treatment decreased the need for initiation of invasive mechanical ventilation and reduced the length of stay in the hospital. However, there were no statistically significant differences in the oxygenation parameter (PaO2/FiO2 ratio and A-a gradient). The improvement in clinically relevant outcomes, without significant differences in specific laboratory outcomes, warrants the conduction of larger trials using sildenafil for the treatment of COVID-19 patients with specific perfusion patterns in sCTA.

Clinical Trial Registration Details: This trial is registered with ClinicalTrials.gov, NCT04489446.

Funding Information: There were no external sources of funding for this investigation.

Declaration of Interests: We declare no competing interests.

Ethics Approval Statement: The study was approved by the ethics committee of Hospital Naval Almirante Nef, and by the ethics committee of Universidad Andres Bello, Chile. All patients provided written informed consent before randomisation.

Suggested Citation

Santamarina, Mario G. and Beddings, Ignacio and Martinez Lomakin, Felipe and Riscal, Dominique Boisier and Claveria, Mónica Gutiérrez and Vidal Marambio, Jaime and Retamal Báez, Nicole and Pávez Novoa, Cristian and Reyes Allende, César and Ferreira Perey, Paulina and Gutiérrez Torres, Miguel and Villalobos Mazza, Camila and Vergara Sagredo, Constanza and Ahumada Bermejo, Sebastian and Labarca Mellado, Eduardo and Barthel Munchmeyer, Elizabeth and Marchant Ramos, Solange and Volpacchio, Mariano and Vega Stieb, Jorge, Sildenafil for the Treatment of Patients With COVID-19 and Perfusion Mismatch on Subtraction Computed Tomography Angiography: A Pilot, Placebo-Controlled Randomised Trial. Available at SSRN: https://ssrn.com/abstract=3887446 or http://dx.doi.org/10.2139/ssrn.3887446

Mario G. Santamarina (Contact Author)

Hospital Naval Almirante Nef - Radiology Department ( email )

Viña del Mar
Chile

Ignacio Beddings

Clinica Bupa Santiago - Radiology Department

Santiago
Chile

Felipe Martinez Lomakin

Hospital Naval Almirante Nef - Intensive Care Unit ( email )

Viña del Mar
Chile

Dominique Boisier Riscal

Hospital Naval Almirante Nef - Intensive Care Unit

Viña del Mar
Chile

Mónica Gutiérrez Claveria

Hospital Naval Almirante Nef - Respiratory Department

Viña del Mar
Chile

Jaime Vidal Marambio

Hospital Naval Almirante Nef - Intensive Care Unit

Viña del Mar
Chile

Nicole Retamal Báez

Hospital Naval Almirante Nef - Intensive Care Unit

Viña del Mar
Chile

Cristian Pávez Novoa

Hospital Naval Almirante Nef - Intensive Care Unit

Viña del Mar
Chile

César Reyes Allende

Hospital Naval Almirante Nef - Intensive Care Unit

Viña del Mar
Chile

Paulina Ferreira Perey

Hospital Naval Almirante Nef - General Internal Medicine Department ( email )

Viña del Mar
Chile

Miguel Gutiérrez Torres

Hospital Naval Almirante Nef - General Internal Medicine Department ( email )

Viña del Mar
Chile

Camila Villalobos Mazza

Hospital Naval Almirante Nef - Infectious Disease Department

Viña del Mar
Chile

Constanza Vergara Sagredo

Hospital Naval Almirante Nef - Intensive Care Unit

Viña del Mar
Chile

Sebastian Ahumada Bermejo

Hospital Naval Almirante Nef - Respiratory Department

Viña del Mar
Chile

Eduardo Labarca Mellado

Hospital Naval Almirante Nef - Intensive Care Unit

Viña del Mar
Chile

Elizabeth Barthel Munchmeyer

Hospital Naval Almirante Nef - Infectious Disease Department

Viña del Mar
Chile

Solange Marchant Ramos

Hospital Naval Almirante Nef - Hospital Pharmacy Department ( email )

Viña del Mar
Chile

Mariano Volpacchio

Centro de Diagnóstico Dr. Enrique Rossi - Radiology Department ( email )

Jorge Vega Stieb

Hospital Naval Almirante Nef - General Internal Medicine Department ( email )

Viña del Mar
Chile