Preliminary data support the effect of Nitric Oxide (NO) on improving the oxygenation in mechanically ventilated patients and spontaneously breathing patients with COVID-19. In vitro studies showed an antiviral effect of NO against SARS-coronavirus. The optimal therapeutic regimen of NO gas in spontaneously breathing hypoxemic patients with COVID-19 is not known. We hypothesize that high concentration inhaled NO with an adjunct of continuous low dose administration between the high concentration treatments can be safely administered in hypoxemic COVID-19 patients compared to the high dose treatment alone. Prolonged administration of NO gas may benefit the patients in terms of the severity of the clinical course and time to recovery. Together with a clinical effect on ventilation-perfusion matching, a prolonged regimen would allow also an increase in antiviral activity (dose and time-dependent).
Coronavirus disease 2019 (COVID-19) consists mainly of a respiratory infection that spans
from a mild involvement of the upper respiratory tract to severe pneumonia leading to
respiratory distress, shock, and death. Fever, cough, and dyspnea/tachypnea, together with
myalgia and fatigue, have been identified as the most common presenting symptoms. Most of the
patients remain in a state of mild upper respiratory tract disease for a relatively long
period (a median of 8-10 days), after which a proportion of up to 25% may develop severe
hypoxemia and ARDS with the necessity of mechanical ventilation. Deterioration with ICU
admission (most likely in older patients with comorbidities) raises the incidence of
mortality in a range that goes from 3.4 up to 61%. Moreover, ICU admission poses a
significant strain in terms of healthcare resources. Thus, a treatment able to avoid the
progression of the disease from the mild to the severe phases would have a substantial
benefit both in terms of lives saved and hospital resources spared. However, at the time,
only Remdesivir and Dexamethasone have shown some benefits in robust clinical trials.
Nitric Oxide gas is a therapy currently approved for the treatment of pulmonary hypertension
in newborns and is also used as rescue therapy in patients with acute respiratory distress
syndrome (ARDS). The clinical role of NO gas in COVID-19 patients could be of particular
relevance since there is in-vitro evidence of NO antiviral activity specifically against SARS
coronavirus. At the time of the SARS pandemic, a small rescue trial on intubated patients
with SARS showed that NO was effective in improving the oxygenation, fasten the resolution of
chest X-ray abnormalities, and improve the clinical outcomes. Moreover, in vitro studies
demonstrated that the NO-donor compound S-nitroso-N-acetylpenicillamine was able to increase
the survival rate of in vitro mammalian cells infected with SARS-CoV. SARS-CoV and SARS-CoV-2
share the same subgenus inside the family Coronaviridae. The literature seems to point
towards an a-specific rather than pathogen-specific antimicrobial effect of NO. Thus, the
role of exogenous inhaled NO as a viricidal agent during COVID-19 infection could be
hypothesized.
Nitric Oxide at high concentration has been found to be microbicidal but still safe in
spontaneously breathing subjects in a phase I trial. There are several trials testing the
efficacy of NO therapy in improving the outcome of COVID-19 patients. So far, only a
retrospective observational study showed that NO gas is useful in improving the oxygenation
in spontaneously breathing patients. However, the optimal therapeutic regimens and the
efficacy of NO gas in improving the oxygenation in hypoxemic COVID-19 patients haven't been
tested.
Drug: Nitric Oxide-Sessions
Nitric Oxide will be delivered at 200 ppm in 2 daily sessions (morning, evening; 9-12 hours apart) for 14 days. Each session will last 30 minutes, for a total of 60 minutes/day for each patient. A tank of NO gas will be connected to the inspiratory limb of the circuit, and the flow will be adjusted to deliver a target concentration of 200 ppm NO. Commercially available tanks will be used to provide the gas. The desired mixture of air, oxygen (O2), and NO will be titrated with the respective flowmeter to reach a concentration of 200 ppm at the inspiratory limb with the desired Fraction of inspired oxygen (FiO2).
Other Name: Nitric Oxide inhalation at high concentration
Drug: Nitric Oxide-Continuous and Sessions
Nitric Oxide will be delivered at 200 ppm in 2 daily sessions (morning, evening; 9-12 hours apart) for 14 days. Each session will last 30 minutes, for a total of 60 minutes/day for each patient. A tank of NO gas will be connected to the inspiratory limb of the circuit, and the flow will be adjusted to deliver a target concentration of 200 ppm NO. Commercially available tanks will be used to provide the gas. The desired mixture of air, oxygen (O2), and NO will be titrated with the respective flowmeter to reach a concentration of 200 ppm at the inspiratory limb with the desired Fraction of inspired oxygen (FiO2).
The subjects assigned to the group "NO High Concentration + Continuous Low Concentration" will receive in adjunction a continuous dose of NO at 20 ppm.
Other Name: Nitric Oxide inhalation at high concentration + low concentration
Inclusion Criteria:
- COVID-19 confirmed by a positive RT-PCR test
- Hospital admission within 11 days from the onset of symptoms
- Spontaneous breathing with oxygen requirement ≥1 L/min
- Expected discharge > 96 hours at randomization
Exclusion Criteria:
- Pregnancy
- Presence of a tracheostomy
- Assistance by any non-invasive CPAP or NIV at the screening
- Treatment with high flow nasal cannula at the screening
- Clinical contraindication to the use of NO
- Patients enrolled in another interventional trial
- Hospitalized and confirmed diagnosis of COVID-19 for more than 7 days
- Previous intubation for COVID-19
- Subject not committed to full support (DNR, DNI or CMO)
- Subject requiring oxygen at home for lung comorbidities
- The primary cause of hospitalization not due to COVID-19
- Subject receiving vasopressor at the time of screening
- History of malignancy or other irreversible disease/conditions with 6-month mortality
>50%
- Oxygen saturation of 100% at screening, despite oxygen requirement
- Patients on dialysis at the time of enrollment
Cardiology Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences
Tomsk, Russian Federation
Nikolay O Kamenshchikov, M.D., Principal Investigator
Cardiology Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences