Almitrine and COVID-19 Related Hypoxemia

COVID-19 Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04380727
• Other study ID #: 2020PI080_2
• Status: Completed
• Start date: March 20, 2020
• Est. completion date: April 25, 2020

Study information

• Verified date: July 2020
• Source: Central Hospital, Nancy, France
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational [Patient Registry]

Clinical Trial Summary

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).

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 17
• Est. completion date: April 25, 2020
• Est. primary completion date: April 14, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• COVID-19
• Hypoxic Respiratory Failure
• Respiratory Insufficiency

Locations

Country	Name	City	State
France	Centre Hospitalier Universitaire NANCY	Vandoeuvre-les-Nancy

Sponsors (1)

Lead Sponsor	Collaborator
Central Hospital, Nancy, France

Country where clinical trial is conducted

France, 

References & Publications (5)

B'chir A, Mebazaa A, Losser MR, Romieu M, Payen D. Intravenous almitrine bismesylate reversibly induces lactic acidosis and hepatic dysfunction in patients with acute lung injury. Anesthesiology. 1998 Oct;89(4):823-30. — View Citation

Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, Qiu Y, Wang J, Liu Y, Wei Y, Xia J, Yu T, Zhang X, Zhang L. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. 2020 Feb 15;395(10223):507-513. doi: 10.1016/S0140-6736(20)30211-7. Epub 2020 Jan 30. — View Citation

Gattinoni L, Coppola S, Cressoni M, Busana M, Rossi S, Chiumello D. COVID-19 Does Not Lead to a "Typical" Acute Respiratory Distress Syndrome. Am J Respir Crit Care Med. 2020 May 15;201(10):1299-1300. doi: 10.1164/rccm.202003-0817LE. — View Citation

Payen DM, Gatecel C, Plaisance P. Almitrine effect on nitric oxide inhalation in adult respiratory distress syndrome. Lancet. 1993 Jun 26;341(8861):1664. — View Citation

Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, Xiang J, Wang Y, Song B, Gu X, Guan L, Wei Y, Li H, Wu X, Xu J, Tu S, Zhang Y, Chen H, Cao B. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020 Mar 28;395(10229):1054-1062. doi: 10.1016/S0140-6736(20)30566-3. Epub 2020 Mar 11. Erratum in: Lancet. 2020 Mar 28;395(10229):1038. Lancet. 2020 Mar 28;395(10229):1038. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Changes from baseline PaO2 (mmHg)	Partial pressure of oxygen in arterial blood	45 minutes after almitrine infusion
Primary	Changes from baseline ScvO2 (%)	central venous oxygen saturation	baseline and 45 minutes after almitrine infusion
Secondary	Changes from baseline PaO2 (mmHg)	partial pressure of oxygen in arterial blood	8 hours
Secondary	Changes from baseline ScvO2 (%)	central venous oxygen saturation	8 hours