Abstract
BackgroundSARS-CoV-2 seems to affect the regulation of pulmonary perfusion. Hypoperfusion in areas of well-aerated lung parenchyma results in a ventilation–perfusion mismatch that can be characterized using subtraction computed tomography angiography (sCTA). This study aims to evaluate the efficacy of oral sildenafil in treating COVID-19 inpatients showing perfusion abnormalities in sCTA.MethodsTriple-blinded, randomized, placebo-controlled trial was conducted in Chile in a tertiary-care hospital able to provide on-site sCTA scans and ventilatory support when needed between August 2020 and March 2021. In total, 82 eligible adults were admitted to the ED with RT-PCR-confirmed or highly probable SARS-COV-2 infection and sCTA performed within 24 h of admission showing perfusion abnormalities in areas of well-aerated lung parenchyma; 42 were excluded and 40 participants were enrolled and randomized (1:1 ratio) once hospitalized. The active intervention group received sildenafil (25 mg orally three times a day for seven days), and the control group received identical placebo capsules in the same way. Primary outcomes were differences in oxygenation parameters measured daily during follow-up (PaO2/FiO2 ratio and A-a gradient). Secondary outcomes included admission to the ICU, requirement of non-invasive ventilation, invasive mechanical ventilation (IMV), and mortality rates. Analysis was performed on an intention-to-treat basis.ResultsTotally, 40 participants were enrolled (20 in the placebo group and 20 in the sildenafil group); 33 [82.5%] were male; and median age was 57 [IQR 41–68] years. No significant differences in mean PaO2/FiO2 ratios and A-a gradients were found between groups (repeated-measures ANOVA p = 0.67 and p = 0.69). IMV was required in 4 patients who received placebo and none in the sildenafil arm (logrank p = 0.04). Patients in the sildenafil arm showed a significantly shorter median length of hospital stay than the placebo group (9 IQR 7–12 days vs. 12 IQR 9–21 days, p = 0.04).ConclusionsNo statistically significant differences were found in the oxygenation parameters. Sildenafil treatment could have a potential therapeutic role regarding the need for IMV in COVID-19 patients with specific perfusion patterns in sCTA. A large-scale study is needed to confirm these results.Trial Registration: Sildenafil for treating patients with COVID-19 and perfusion mismatch: a pilot randomized trial, NCT04489446, Registered 28 July 2020, https://clinicaltrials.gov/ct2/show/NCT04489446.
Highlights
SARS-CoV-2 seems to affect the regulation of pulmonary perfusion
Severe gas-exchange impairment can occur in even the early stages, with only minor lung airspace disease appearing in CT images [2]
Local nitric oxide (NO) depletion leads to vasoconstriction, which establishes a progressive V/Q mismatch with extensive areas of well-aerated lung parenchyma in CT images but hypoperfused in subtraction CT angiography images, that function as alveolar dead space [7]. These findings suggest that evaluation of therapies oriented to improve pulmonary perfusion in the early phases of mild to moderate COVID-19 pneumonia should be considered
Summary
SARS-CoV-2 seems to affect the regulation of pulmonary perfusion. This study aims to evaluate the efficacy of oral sildenafil in treating COVID-19 inpatients showing perfusion abnormalities in sCTA. More than 247 million infections and more than 5 million deaths due to SARS-CoV-2 have been reported worldwide [1]. Vaccines have been developed in record time, and already more than 6893 million vaccine doses have been administered worldwide, there is still a long time until global immunity [1]. Most patients infected with the SARS-CoV-2 virus develop a self-limiting infection and present with mild symptoms or appear asymptomatic. Up to 20% of patients may develop a rapid progression to acute hypoxemic respiratory failure, leading to ventilation support, admission to the intensive care unit (ICU), and eventually death [2]. Severe gas-exchange impairment can occur in even the early stages, with only minor lung airspace disease appearing in CT images [2]
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