Abstract: In severe COVID-19 pulmonary failure, hypoxia 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 to improve oxygenation.
Patients and Method. A case control series of 17 confirmed COVID-19 mechanically ventilated patients in prone or supine positioning was collected: 10 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 intrapulmonary shunt increasing the PaO 2 and ScvO 2 .
Results Patients were male (59%) with median (25 th , 75th percentiles) age of 70 (54-78) years and a BMI of 29 (23-34). At stable mechanical ventilatory settings, PaO 2 (mmHg) at FiO 2 1 (135 (85, 195) to 214 (121, 275); p = 0.06) tended to increase with almitrine. This difference was significant when the best PaO 2 between the 2 doses was used : 215 (123,294) vs baseline (p = 0.01). A concomitant increase in ScvO 2 occurred ((73 (72, 76) to 82 (80, 87); p = 0.02). Eight over 10 almitrine-treated patients increased their PaO 2 , with no clear dose-effect. During the same time, the controls did not change PaO 2 .
In conclusion, in early COVID-19 with severe hypoxemia, almitrine infusion is associated with improved oxygenation in prone or supine positioning. This pharmacological intervention may offer an alternative and/or an additional effect to proning and might delay or avoid more demanding modalities such as ECMO.
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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. (1, 2) The lung contamination by SARS-CoV-2 is typically characterized by a major difficulty to oxygenate the arterial blood. (3) This severe hypoxemia is associated with preserved respiratory mechanical properties, in particular the pulmonary system compliance. As recently quoted by Gattinoni et al (4) , the COVID-19 pneumonia seems to have 2 different phenotypes: the early phase, with severe hypoxemia and close to normal respiratory mechanics with a moderate effect of PEEP on lung recruitment; the later phase, corresponding to the more "classic" ARDS alteration of respiratory mechanics such as a reduced compliance with chest CT Scan images of diffuse ground-glass opacities and condensations. The hypoxia during the early phase seems to mainly result from an important ventilation/perfusion (VA/Q) mismatch(5) 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". (2) Most of the publications on severe COVID-19 describe intubated and mechanically ventilated patients, installed in prone positioning as an adjuvant therapy to limit hypoxia. The prone positioning in ARDS is supposed to facilitate alveolar recruitment, and to decrease the heterogeneity of compliance.(6) In theory, this modality should have a limited effect during the COVID-19 early phase. The recent publications demonstrated that the majority of patients improved PaO 2 after prone positioning,(7) which suggests another mechanism to improve PaO 2 .
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The most probable was a pulmonary blood flow redistribution towards the ventilated areas by gravitational forces. This modality creates a huge work load to the care team, and increases the risk of endotracheal tube obstruction and malposition, and pressure sores on face and chest. (6) In the 90s', other non-ventilatory strategies have been reported including inhaled nitric oxide(8), almitrine bismesylate (9, 10) or a combination of both.(11) According to the French National agency for Drug Security (ANSM), only iv almitrine was indicated for hypoxic acute respiratory failure as Drug of Major Therapeutic Interest. The brutal COVID-19 outbreak with many severe hypoxic patients prompted intensivists to test iv almitrine to improve HPV(12, 13) and to reduce the intrapulmonary shunt. The use of ECMO is limited to trained centres, which could not meet COVID-19-related demands. We hypothesized that almitrine might restore even partially a HPV response, both in supine or prone positioning.
We investigated 10 COVID-19 patients mechanically ventilated at FiO 2 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 were compared with 7 controlmatched COVID-19 patients treated conventionally. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)
The copyright holder for this preprint this version posted May 22, 2020. . https://doi.org/10.1101/2020.05.18.20105502 doi: medRxiv preprint 6 objections to use almitrine and collected data for scientific purposes and/or potential publications or not. The statement including also the opposition forms was dated and recorded in medical file.
The study was retrospectively registered at ClinicalTrials.govafter enrolment (NCT04380727, Principal Investigator: Marie-Reine LOSSER, M.D., Ph.D., May 7, 2020, Between March16 and April 12, 2020, COVID-19 patients referred to ICU were screened to receive iv almitrine using the following criteria: a positive RT-PCR, a highly suggestive thoracic CTScan, and a severe hypoxemia leading to intubation for less than 3 days. The exclusion criteria . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
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Data were reported as median (25th-75th percentiles) for continuous variables and as count (percentage) for categorical variables. Change in blood gases parameters during almitrine infusion were first assessed using a Friedman test followed by a pairwise Wilcoxon signed-ranks post-hoc test with Bonferroni correction when appropriate. Second, to perform a two-points comparison (i.e. baseline and after almitrine infusion) with the control group (baseline and H8 measurement), we only considered the best variation in term of PaO 2 regardless of the infusion dose of almitrine (4 or 12 mcg/kg/min). In the two groups, difference between before (baseline) and after (almitrine infusion or H8) measurement was assessed using a Wilcoxon signed-ranks test. All tests were 2-sided and a p value <0.05 was considered as statistically significant.
Statistical analyses were performed using R version 3.6.0 for Mac OS (The R Foundation for Statistical Computing, Vienna, Austria).
All patients had a confirmed diagnosis of COVID-19 (positive PCR testing). The median age was 70 (54-78) years, with 10/17 males, having a median BMI of 29 (23-34). Haemoglobin was stable at 12.2 (8.9-13.8) g/dL. Most of the patients were intubated just before or soon after ICU admission. Patients from both groups had co-morbidities, mostly metabolic and/or cardiovascular diseases under chronic treatment (Table 1 ). At the time of manuscript submission, in almitrine group 2 patients died and 6 patients were extubated and discharged from the ICU, the remaining being still mechanically ventilated. In the control group, 2 died and 5 were extubated and discharged from the ICU.
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The copyright holder for this preprint this version posted May 22, 2020. . https://doi.org/10.1101/2020.05.18.20105502 doi: medRxiv preprint Table 2 shows the hemodynamic, gas exchange and mechanical ventilation parameters from baseline, 4 and 12 mcg/kg/min of almitrine infusion. PaO 2 tended to increase (p = 0.06) with a significant increase in ScvO 2 (p =0.03). All other parameters did not change during the protocol.
The changes in PaO 2 did not parallel the increasing doses of almitrine (data not shown). In the control COVID group, none of the collected parameters changed after 8hrs (Supplementary table   S1 ). The whiskers box plot of Figure 1 shows the median PaO 2 /FiO 2 for almitrine and control groups. The best response in PaO 2 increase starting from baseline was found significant only in the almitrine-treated group (p = 0.01), while it remained stable in controls. Figure 2 shows the individual data for both PaO 2 and ScvO 2 in both groups, which significantly increased only in the almitrine group. Eight over 10 patients increased their PaO 2 with almitrine, with no clear relation with the level of infusion rate. Of note, when the drug was available to continue, the increase in PaO 2 associated with almitrine infusion persisted (3 patients), which permitted to reduce the number of positioning changes. During this short perfusion time no hemodynamic side effects were observed and lactate remained stable (<1.5 mmol/L) (data not shown).
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others have shown that almitrine may spectacularly improve PaO 2 by reducing the intrapulmonary oxygen shunt. (5, 13) In the present pilot study, almitrine was used as a test to restore, even though partially, the HPV in supine or prone positioning (Fig 2B) . The combination of these conditions (prone and almitrine) could then be seen as a combination of gravitational and This case control series has several limitations in addition to the small size cohort (17 patients). First, although the "control" COVID-19 patients were selected on stringent criteria to match the studied group, it was not randomized and could be biased. The stability in PaO 2 during 8 hours reinforced the credence in an almitrine effect. In absence of a drug shortage, all of these patients would have received almitrine. This shortage resulted from the small national stock of almitrine facing an important demand during the pandemic. Second, although the data were prospectively collected, the overwhelmed care team capabilities in a dramatic context explains why some data were missing. Third, for the same reason, we were not able to administer the drug . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
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for a longer period than 36 to 48 hours for few patients. This precludes any conclusion about the potential benefit on mechanical ventilation duration and on the number of prone positioning.
Following the same line of thinking, the almitrine test on arterial oxygenation cannot be proposed as either a prognostic test or a predicator of the prone position response.
In conclusion, in a case series of early hypoxemic COVID-19 pneumonia with acute respiratory failure, iv almitrine was associated with an improvement in arterial blood oxygenation both in prone or supine positioning in most of the patients, suggesting a partial recovery of the pulmonary vessels' contractility. This pharmacological intervention may offer an alternative and/or an additional strategy to the prone positioning in severe COVID-19 ARDS. It may help to support the lung function when ECMO possibilities are very limited.
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