This randomized controled open label clinical trial conducted in patients with hypoxemic respiratory failure admitted to the ICU and requiring ventilatory support (invasive or non-invasive) is to evaluate whether treatment with cyproheptadine, a serotonin receptor antagonist, compared to usual care, increases the number of ventilator-free days.

Some studies have shown increased platelet activation and reactivity in patients with COVID-19. This platelet activation is associated with serotonin release. Some characteristics observed during the evolution of COVID-19 may be associated with these increased levels of serotonin. In this scenario, the antagonism of the action of serotonin could improve the clinical course of patients affected by COVID-19. Cyprohepatdine is an anti-serotonergic antihistamine drug with a long track record of safety and tolerability.

Investigators will randomize 274 patients who have tested positive for COVID-19 and who will be admitted to the ICU requiring ventilatory support (invasive or non-invasive).

Patients will be randomized to a 1:1 ratio for receiving usual care + cyproheptadine (8mg three times a day for 10 days) or usual care.

Patients will be followed until discharge to determine length of stay in the ICU and hospital, mortality in the ICU and hospital and days free from ventilatory support during the first 28 days.

Inclusion Criteria:

• Positive PCR for SARS-Cov-2
• ICU admission < 48 hours
• Age 18 years or older
• Need for invasive or non-invasive ventilatory support (non-invasive ventilation or high-flow nasal cannula) < 48 hours

Exclusion Criteria:

• Pregnancy or breastfeeding
• Refusal to sign the informed consent form
• Expected death in the next 24 hours
• Patients taking routinely SSRI or monoamine oxidase inhibitor therapy
• Impossibility of using the enteral route
• History of seizure disorder
• History of adverse reaction to antihistamines or to cyproheptadine
• Readmission to the ICU