key: cord-0730929-3ct81dxl authors: McFadyen, Charles; Garfield, Ben; Mancio, Jennifer; Ridge, Carole A.; Semple, Tom; Keeling, Archie; Ledot, Stephane; Patel, Brijesh; Samaranayake, Chinthaka B.; McCabe, Colm; Wort, S John; Price, Susanna; Price, Laura C. title: Use of sildenafil in patients with severe COVID-19 pneumonitis date: 2022-04-15 journal: Br J Anaesth DOI: 10.1016/j.bja.2022.04.004 sha: e6b565a7d60d2b4ed33b5b13a0294ffb76d36c85 doc_id: 730929 cord_uid: 3ct81dxl nan Sildenafil-treated patients with COVID-19 pneumonitis and moderate to severe ARDS were studied between 1 st March 2020 and 31 st May 2020. The study had ethical approval (A-CLUE 285452, IRAS reference 285452). Oxygenation and carbon dioxide (CO2) clearance were assessed immediately prior, 24 h, 48 h, and 5 days after sildenafil by averaging three blood gas and ventilator parameters to calculate P:F ratio (PaO2:FIO2), oxygenation index (10) , dead space fraction (11) and ventilatory ratio (12) . Vasoactive drug dose was calculated using norepinephrine equivalents (NE) (13) and the vasoactive-inotropic score (VIS) (14) . Initial sildenafil at 12.5 mg TDS was titrated up to 25 mg TDS if tolerated. Patients underwent baseline and follow-up computed tomography (CT) scanning (some with dual energy CT pulmonary angiogram (DECTPA), Supplementary material) and detailed echocardiographic assessment, e.g. pulmonary vascular resistance (PVR) using the velocity time integral of the pulsed wave doppler at the RV outflow tract (supplementary material). Twenty-five patients (73% male) were included, mean age 54.1 (SD 9) yr; 10 were on veno-venous extra-corporeal membrane oxygenation (VV-ECMO), and 11 were proned ( Table 1) . Baseline echocardiography suggested pulmonary hypertension and/or RV dysfunction in all patients. Sildenafil was introduced at 6.4 (3.2) days of inhaled NO therapy in some patients to aid weaning of NO (n=15). Sildenafil was administered orally via nasogastric tube at 12.5 mg TDS (n=14) or 25 mg TDS (n=8) or intravenously (10 mg TDS (n=2) or 1 mg h -1 infusion (n=1)) depending on clinician choice and absorption issues. One patient weaned sildenafil prior to ICU discharge; 23 patients continued sildenafil for 12.7 (range 1-60) days at 25 mg TDS. Norepinephrine equivalents and vasoactive-inotropic score increased 24 h following initiation of sildenafil therapy (Table 1) . Norepinephrine doses increased in 14, decreased in 10, and remained unchanged in 1 patient. Mean arterial pressure (74.9 (5.8) to 74.7 (5.1) mm Hg, p=0.9) and heart rate (82.8 (15.4) to 86.9 (17.6) bpm p=0.09) were stable 2 4h following sildenafil. ECMO patients were on lower initial doses but had significant increases following sildenafil initiation (0.06 (0.04) to 0.09 (0.06) J o u r n a l P r e -p r o o f µg.kg -1 .min -1 ; p=0.02). There was no haemodynamic instability as a direct result of sildenafil that necessitated treatment discontinuation. The P:F ratio increased in non-ECMO patients from 17.7 (5.9) to 20.9 (6.0) kPa (p<0.01) ( Table 1 Table) . We report outcomes with sildenafil in a well characterized cohort of ARDS patients with pulmonary hypertension or RV dysfunction due to COVID-19. While a single sildenafil dose can cause hypotension and deterioration in oxygenation in ARDS (without associated pulmonary hypertension or RV dysfunction), this study suggests sildenafil was well tolerated in COVID-19 ARDS, without a deterioration in oxygenation, dead space or haemodynamics, and improved cardiac biomarkers and echocardiographic features. Several factors further to dosing may explain the potential beneficial effects in this cohort. Pulmonary vascular and RV dysfunction are common in COVID-19 ARDS. Increased cardiac output due to reduced pulmonary vascular resistance and improved RV function, as supported by improvement in cardiac biomarkers, may have augmented oxygen delivery. Gas exchange did not deteriorate with sildenafil, suggesting that intrapulmonary shunt or potential ventilation-perfusion mismatch was balanced by beneficial effects (e.g. on cardiac output). The potential for improvement in longer term lung function impairment (15) remains to be seen. This report is of course limited by its retrospective and nonrandomised nature. Despite limitations, our results suggest that sildenafil is safe in carefully selected COVID-19 ARDS patients. Supporting these observations, a recent randomised trial of sildenafil reported reduced hospital stay and need for mechanical ventilation in ward patients with COVID-19 and perfusion deficits on DECTPA (not selected for RV dysfunction) (16) . These developments are encouraging given that a pulmonary vasculopathy appears central to the pathophysiology of severe acute COVID-19, and sildenafil therapy merits further exploration in randomised trials. J o u r n a l P r e -p r o o f Viral presence and immunopathology in patients with lethal COVID-19: a prospective autopsy cohort study Pulmonary Vascular Dilatation Detected by Automated Transcranial Doppler in COVID-19 Pneumonia Pulmonary Angiopathy in Severe COVID-19: Physiologic, Imaging, and Hematologic Observations Right ventricular dysfunction in critically ill COVID-19 ARDS Potential for personalised application of inhaled nitric oxide in COVID-19 pneumonia A Study of 3CLpros as Promising Targets against SARS-CoV and SARS-CoV-2. Microorganisms Nintedanib and Sildenafil in Patients with Idiopathic Pulmonary Fibrosis and Right Heart Dysfunction. 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