Compassionate use of pulmonary vasodilators in acute severe hypoxic respiratory failure due to COVID-19

ABSTRACT

Introduction: There have been over 200 million cases and 4.4 million deaths from Covid-19 worldwide. In the UK over half a million have required hospitalisation, with over 130,000 deaths. Although most experience a mild illness the mortality can be over 50% for those requiring mechanical ventilation.1 One potential treatment for severe hypoxaemia is inhaled pulmonary vasodilator (IPVD) therapy, either as nitric oxide (NO) or prostaglandin analogues. Despite the lack of robust evidence IPVDs are often considered recue treatments for refractory hypoxaemia.2,3 Given the disease severity in COVID-19 we implemented a protocol for the use of IPVDs on a compassionate basis for patients with severe hypoxaemia receiving otherwise maximal support. In this study we detail our findings and assess differences between survivors and non-survivors. Objectives: The primary outcome of this study was percentage changes in PaO2/FiO2 (PF) ratio and Alveolararterial (A-a) gradient at 2, 6, 12, 24, 48 and 72 hours following initiation of IPVD therapy. Secondary outcomes were differences in characteristics and response to therapy between survivors and non-survivors who received an IPVD. Methods: Data from a prospectively maintained research database of patients with SARS-CoV-2 admitted to the ICU at a large teaching hospital were analysed for the time period 14 March 2020 -11 February 2021. Patients aged 18 years or older who received an IPVD during their admission were eligible for inclusion. An IPVD was considered if the PF ratio was less than 13.3kPa despite rescue therapies (prone positioning, neuromuscular blockade, airway pressure release ventilation). Nitric oxide was commenced at 20ppm and titrated to response. If oxygenation improved Iloprost nebulisers were commenced at 10-30mcg four hourly and NO weaned. Results: Three-hundred eight patients with SARS-Cov-2 were admitted during the study period of whom 59 (19.2%) received IPVD therapy. Patients receiving an IPVD had a lower PF ratio (14.37 vs. 16.37kPa, p=0.002) and higher APACHE-II score (17 vs. 13, p=0.028) at admission compared to those who did not. Survival to ICU discharge was lower in patients receiving an IPVD (55.9% vs. 81.9%, p<0.001). The median PF ratio at commencing IPVD therapy was 11.33kPa (9.93-12.91) with a median of 6 days from admission to receiving an IPVD. At 72 hours the median improvement in PF ratio was 33.9% (-4.3-84.1). In patients receiving IPVDs there were no differences in other therapies received (steroids, prone ventilation, ECMO) between survivors (n=33) and non-survivors (n=26), with the exception of renal replacement therapy. At 72 hours changes in PF ratio (70.8 vs. -4.1%) and reduction in A-a gradient (44.7 vs. 14.8%) differed significantly between survivors and non-survivors (both p <0.001). Conclusion: The response to the compassionate use of IPVDs for patients with acute hypoxic respiratory failure due to Covid-19 differs significantly between survivors and non-survivors. Both NO and inhaled prostaglandins may offer therapeutic options for severe hypoxaemia due to COVID-19, with prostaglandins particularly attractive as they do not require specialist delivery systems. The use of inhaled prostaglandins, and NO where feasible, should be studied in both isolation and combination in adequately powered prospective randomised trials.