Almitrine and COVID-19 Related Hypoxemia

Study Overview
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Brief Summary
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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).

Detailed Description
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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.

Official Title
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Almitrine and Severe COVID-19 Patients in ICU [Almitrine et Patients COVID-19 en Reanimation (French)]

Conditions
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COVID-19, Hypoxic Respiratory Failure

Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Almitrine<br>Administration of 4 mcg/kg/min iv almitrine bismesylate (Vectarion®, Servier Laboratory, France), over 30-45 min followed by 12 mcg/kg/min infusion rate. Because of a shortage of drug store at national level, a protocol using continuous infusion was not considered. Some patients may receive the drug for 36 hours depending on availability.. | |
| Control<br>To eliminate the eventuality of a spontaneous evolution of hypoxia, these patients were matched to control COVID-19 patients treated without almitrine (time control). | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes from baseline PaO2 (mmHg) | Partial pressure of oxygen in arterial blood | 45 minutes after almitrine infusion | 
| Changes from baseline ScvO2 (%) | central venous oxygen saturation | baseline and 45 minutes after almitrine infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes from baseline PaO2 (mmHg) | partial pressure of oxygen in arterial blood | 8 hours | 
| Changes from baseline ScvO2 (%) | central venous oxygen saturation | 8 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hypoxic pulmonary vasoconstriction, Prone position, intra-pulmonary shunt, SARS-CoV-2