In severe COVID-19 pulmonary failure, the profound hypoxemia is mainly related to pulmonary vasodilation with altered hypoxic pulmonary vasoconstriction (HPV). Besides prone positioning, other non-ventilatory strategies may reduce the intrapulmonary shunt. This study has investigated almitrine, a pharmacological option used in standard care to improve oxygenation.

A case control series of mechanically ventilated confirmed COVID-19 patients was recorded.

At stable ventilatory settings, consecutive patients received two doses of almitrine (4 and 12 mcg/kg/min) at 30-45 min interval each, and were compared to 7 "control" COVID-matched patients conventionally treated.

The end-point was the reduction of intra-pulmonary shunt, with an increase in partial pressure of arterial oxygen (PaO2) and central venous oxygen saturation (ScvO2).

The clinical presentation of COVID-19 disease is heterogenous, ranging from no symptoms to severe acute respiratory failure (ARF), which may have a poor prognosis. A severe hypoxemia is associated with preserved respiratory mechanical properties, in particular the pulmonary system compliance.

The hypoxia during the early phase seems to mainly result from an important ventilation/perfusion (VA/Q) mismatch associated with an altered pulmonary vasoconstriction. The "protective" mechanism called hypoxic pulmonary vasoconstriction (HPV) normally reduces the blood flow in poorly or non-ventilated areas towards aerated zones leading to reduce the (VA/Q) mismatch. HPV seems poorly functional in COVID-19 severe patients in absence of "cor pulmonale".

According to the French National agency for Drug Security (ANSM, Paris, France), only iv almitrine is indicated for hypoxic acute respiratory failure as Drug of Major Therapeutic Interest. This molecule is a routine option in the treatment strategy of severe hypoxemia.

The investigators studied COVID-19 patients mechanically ventilated at FiO2 1 with a severe intrapulmonary shunt during their early phase. The emergency conditions and the acute high inflow of patients to ICU impeded the design of a randomized control trial. To eliminate the eventuality of a spontaneous evolution of hypoxia, these patients will be compared with control-matched COVID patients treated conventionally.

Inclusion Criteria :

• a positive RT- PCR,
• a highly suggestive thoracic CTScan, and
• a severe hypoxemia leading to intubation for less than 3 days
• mechanically ventilated at FiO2 1 with a severe intrapulmonary shunt during their early phase

Group : patient who has been treated with almitrine (4 mcg/kg/min iv almitrine bismesylate (Vectarion®, Servier Laboratory, France) then 12 mcg/kg/min infusion rate) during their hospital treatment.

Control group : Matched COVID-19 patients, on gender, age, BMI and duration of mechanical ventilation, with serial measurements corresponding to the duration of almitrine testing (8 hours), with same inclusion and exclusion criteria.

Exclusion Criteria:

• the presence of an acute cor-pulmonale on the trans-thoracic 2D Echo-Doppler
• abnormal liver function tests
• hyperlactatemia

Between March16 and April 20, 2020, COVID-19 patients referred to ICU age, gender, BMI, Hb The recorded parameters were: the ventilatory settings unchanged along the protocol, including FiO2, PEEP level, tidal volume (VT), peak inspiratory pressure, plateau pressure; haemoglobin concentration, blood gases simultaneously sampled on the arterial catheter and on the central catheter to assess central venous oxygen saturation SvcO2, and arterial lactate, right atrial pressure; cardiac output when possible (Mostcare®, Vygon, Ecouen, France).

Collaborative register on COVID-19 having benn treated with almitrine