key: cord-328996-3sf2i45r
authors: Barthélémy, Romain; Blot, Pierre-Louis; Tiepolo, Ambre; Le Gall, Arthur; Mayeur, Claire; Gaugain, Samuel; Morisson, Louis; Gayat, Etienne; Mebazaa, Alexandre; Chousterman, Benjamin Glenn
title: Efficacy of Almitrine in The Treatment of Hypoxemia in Sars-Cov-2 Acute Respiratory Distress Syndrome
date: 2020-06-06
journal: Chest
DOI: 10.1016/j.chest.2020.05.573
sha: 
doc_id: 328996
cord_uid: 3sf2i45r

nan

AM received speaker's honoraria from Novartis, Orion, and Servier and fees as a member of the advisory board and/or steering committee from Adrenomed, Sanofi, Roche, Abbott, and 4TEEN4. BC received fees as a member of an advisory board from Roche Diagnostics. The other authors have not disclosed any potential conflict of interest.

Research Letter 1 Dear Editor, 2 Critically ill Covid-19 patients frequently present profound hypoxemia with Acute 3

Respiratory Distress Syndrome (ARDS) requiring mechanical ventilation (MV) 1 . According to 4 recently published Covid-19 guidelines 2 , ventilatory support aims at increasing alveolar 5 oxygen partial pressure with non-invasive methods and eventually MV. Ventilator settings 6 are optimized in order to recruit collapsed alveoli and reduce ventilator-induced lung injury. 7

However, in Sars-Cov-2 ARDS, it has been hypothesized that recruitment strategies may be 8 hazardous because of a preserved compliance 3 and a poor response to PEEP 4 whereas 9 physiological measurements rather show increased intrapulmonary shunt 5 . Abnormal 10 pulmonary vascular dilation and increased perfusion surrounding areas of lung opacity have 11 been identified with dual-energy CT imaging, suggesting that insufficient hypoxic pulmonary 12 vasoconstriction (HPV) may plays a major role in the onset of hypoxemia 6 . 13

Almitrine, a drug that used to decrease intrapulmonary shunt by enhancing HPV, improves 14 gas exchange in ARDS 7 . We hypothesized that almitrine could improve hypoxemia in Sars-15

Cov-2 ARDS patients. 16

This monocenter retrospective study aimed to evaluate the association between almitrine 19 introduction and improvement of oxygenation in Sars-Cov-2 ARDS. The study was conducted 20 in a 36-bed ICU (Hôpital Lariboisière, Paris, France) fully dedicated to the Covid-19 outbreak. 21 4

The medical records of all patients admitted between March 14 th 2020 and April 11 th 2020 22 were reviewed. 23

Inclusion criteria in the study were: admission for respiratory failure, a diagnosis of ARDS 24 according to Berlin criteria 8 , laboratory confirmed Sars-Cov-2 infection, almitrine infusion in 25 ICU. The primary endpoint was the arterial oxygen partial pressure (PaO 2 ) to fraction of 26 inspired oxygen (FiO 2 ) ratio between baseline value and peak value during the 1 st -6 th hour 27 timeframe after introduction of almitrine. PaO 2 /FiO 2 ratio was measured with FiO 2 1. The 28 other endpoints were incidence of treatment failure at 24h, 48h, 72h and 96h, and safety. 29

Treatment failure was defined as death, or the need for additional rescue therapy. Increase 30 in right atrial pressure (RAP) and lactate during the first 6 hours and peak values for liver 31 tests during the first 48h were reported as safety data. 32

This study was approved by an institutional ethics committee: Institutional Review Board 33 (IRB 00006477) of HUPNVS, Paris 7 University. 34

Patients were managed according to local protocol based on international guidelines 9 . 36

Intrapulmonary shunt is confirmed after exclusion of a patent foramen ovale. Pleural 37 effusions are considered for drainage. Hemodynamic optimization is performed to address 38 low PvO 2 effect. Early respiratory management includes limitation of tidal volume and 39 plateau pressure, systematic neuromuscular blockade and prone positioning session of at 40 least 16h. PEEP is individualized to improves oxygenation without deteriorating compliance 41 and cardiac output. In case of persistent refractory hypoxemia, we usually consider almitrine 42 infusion (initial dose 2 µg.kg −1 .min −1 ) and/or inhaled nitric oxide (iNO). Almitrine and iNO use 43 are decided after collegial discussion on a case-by-case basis. If severe hypoxemia persists 44 despite the latter treatments, extracorporeal membrane oxygenation (ECMO) team is called 45 to evaluate the indication of the device. 46

Continuous variables before and after almitrine infusion were compared by a Wilcoxon Rank 48

Sum test for paired data. All statistical analyses were performed using R statistical software 49 version 3.6.1. 50

Patients 52

Eighty-six patients were admitted to our ICU during the studied period. Nineteen of the 20 53 patients that met inclusion criteria had complete data and were analyzed ( Eighteen patients (95%) had at least one session of prone positioning before almitrine. 59

The median PaO 2 /FiO 2 ratio increased from 79 [64-100] at baseline to 117 [81-167] after 61 almitrine (p=0.001) (Figure 1 ). 62 

This is the first study describing therapeutic effects of almitrine in Sars-Cov-2 ARDS. In our 73 observational study, almitrine was associated with an increase in PaO 2 /FiO 2 ratio after 74 treatment. However, this improvement of hypoxemia seems to be heterogenous amongst 75 patients. Furthermore, despite an associated improvement in PaO 2 /FiO 2 ratio, the majority 76 of patients receiving almitrine went on to needing additional rescue interventions or died. 77 This may be explained by the fact that, in our study, almitrine has been used as a rescue 78 therapy in severe patients with worsening hypoxemia and very low PaO 2 /FiO 2 ratio. 79

Even though this is a small sample study without control group, our data shows that 80 enhancing HPV is an encouraging strategy to reduce hypoxemia in Sars-Cov-2 ARDS. This 81 could at least be helpful to secure intra-or inter-hospital transfers in the most severe 82 patients, or gain precious time until a more invasive life support is available. 83

The ideal time to start almitrine also remains to be determined. Almitrine could be used 84 earlier in the treatment of Sars-Cov-2 hypoxemia to reduce the need or duration of MV, a 85 scarce resource in the setting of worldwide outbreak. However, improvement in hypoxemia 7 is not necessarily associated with improved outcome. On the other hand, almitrine has been 87 identified as a potential candidate against targeted proteins of SARS-Cov-2 with expected 88 inhibitory effect 10 . Altogether, we believe that almitrine should be evaluated in clinical trials 89 aiming at improving patient centered outcome for Covid-19 patients. 90

In this monocenter retrospective study, we found that almitrine at the dose of 2 92 µg.kg −1 .min −1 was associated with an increased PaO 2 /FiO 2 ratio in the following 6 hours in 93

Sars-Cov-2 ARDS patients. 94 12 -Cumulative Incidence of Treatment Failure (n)

Baseline Characteristics and Outcomes of 96

Patients Infected With SARS-CoV-2 Admitted to ICUs of the Lombardy Region

Surviving Sepsis Campaign: guidelines on 99 the management of critically ill adults with Coronavirus Disease

COVID-19 pneumonia: different respiratory 102 treatments for different phenotypes? Intensive Care Med

Lung Recruitability in SARS-CoV-2 Associated Acute 105

Respiratory Distress Syndrome: A Single-center, Observational Study

Analysis of therapeutic targets for SARS-CoV-2 and 123 discovery of potential drugs by computational methods