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Inhaled Nitric Oxide Preferred to Epoprostenol in COVID-19 as Rescue Therapy

The FLARE Four

  • Inhaled nitric oxide (iNO) can result in short-term improvement in oxygenation in patients with acute respiratory distress syndrome, but there is no evidence of a significant effect on mortality, and its use has been linked to renal injury
  • iNO is postulated to have direct antiviral effects but that is unproven in humans
  • In its treatment guidance for critically ill patients with COVID-19, Massachusetts General Hospital reserves iNO as a rescue therapy for patients with refractory hypoxemia, preferring it to nebulized epoprostenol

Massachusetts General Hospital recommends reserving inhaled nitric oxide (iNO) as a rescue therapy for COVID-19 patients with acute respiratory distress syndrome (ARDS) in its treatment guidance for critically ill patients. A fast literature update posted on March 30, 2020, by Tiara Calhoun, MD, internal medicine/global medicine resident, and Charles Corey Hardin, MD, PhD, physician in the Division of Pulmonary and Critical Care Medicine at Mass General discusses the rationale for this decision.

iNO for ARDS Generally

Nitric oxide, a potent and rapid-acting vasodilator, selectively dilates vessels associated with well-ventilated alveoli and thereby improves ventilation–perfusion matching.

Using iNO can result in short-term improvement in oxygenation, but a 2016 Cochrane Review did not find a significant effect on mortality. Most deaths from ARDS are caused not by hypoxemia but by multiorgan failure driven by inflammatory processes.

According to both the Cochrane Review and a 2014 meta-analysis published in Critical Care Medicine, use of iNO increases the risk of renal injury.

iNO for ARDS Related to Coronaviruses

  • Improved oxygenation: The 2002–2003 SARS epidemic was linked to SARS-CoV, a coronavirus genetically similar to SARS-CoV-2. In a pilot study during that epidemic, low-dose iNO was associated with improved arterial oxygenation and decreased duration of mechanical ventilation
  • Antiviral effects: iNO has demonstrated in vitro activity against a wide range of viruses, including SARS-CoV. A number of clinical trials—some at Mass General—are currently examining the effect of iNO on mortality from COVID-19 and clearance of SARS-CoV-2

Choice of Pulmonary Vasodilators

According to Mass General's guidance, iNO should be reserved as rescue therapy for persistent hypoxemia (SaO2 < 90%, PaO2 < 60 mmHg) unresponsive to PEEP titration and prone ventilation. iNO is preferred to epoprostenol because the latter is nebulized and requires an inline filter that must be changed every four hours, which increases the number of times the ventilator circuit must be opened and increases risk of viral transmission to staff.

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Mass General has launched a COVID-19 clinical trials platform that pairs its infectious disease and immunology experts with organ-specific physiology and clinical care leaders to rapidly implement and conduct new investigator- and industry-initiated clinical trials.