Lung Injury (Pulmonary Edema) in COVID-19: Treatment With Furosemide and Negative Fluid Balance (NEGBAL)

Study Overview
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Brief Summary
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In COVID-19, pulmonary edema has been attributed to cytokine storm. However, it is known that SARS-CoV-2 promotes angiotensin-converting enzyme 2 deficiency, it increases angiotensin II and this triggers volume overload. The current study is based on patients with COVID-19, tomographic evidence of pulmonary edema and volume overload. These patients received a standard goal-guided diuretic (furosemide) treatment: Negative Fluid Balance (NEGBAL) approach. This retrospective observational study consists of comparing two groups. The cases show patients with COVID-19 and lung injury treated with NEGBAL approach comparing it to the control group consisting of patients with COVID-19 and lung injury receiving standard treatment. Medical records of 120 critically ill patients (60 in NEGBAL group and 60 in control group) were reviewed: demographic, clinical, laboratory, blood gas and chest tomography (CT) before and during NEGBAL. Once NEGBAL strategy started, different aspects were evaluated: clinical, gasometric and biochemical evolution until the 8th day, tomography until the 12th day, ICU stay, hospital stay and morbidity and mortality until the 30th day.

Detailed Description
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In December 2019, a new coronavirus, known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in Wuhan, China and spread throughout the world. In COVID-19, pulmonary edema has been described; however, the dominant paradigm is focused on cytokine storm as responsible for lung injury and subsequent acute respiratory distress syndrome (ARDS). Not everyone agreed with this paradigm. Sinha et al. challenged the role of this cytokine storm given that median interleukin-6 (IL-6) levels in non-COVID patients ARDS were up to 200 times higher than in patients with severe COVID-19. Gattinoni et al. maintained that COVID-19 presented as an atypical form of ARDS. On the other hand, Kuba et al. and Imai et al. reported that angiotensin-converting enzyme 2 (ACE2) levels during a SARS-CoV infection are decreased. Furthermore, in patients with COVID-19, plasma levels of Angiotensin II are higher than in healthy population and stimulate an upregulation of aldosterone level, triggering sodium and water retention. SARS-CoV-2 enters through ACE2 and downregulates ACE2 expression so that this enzyme is unable to exert its protective effects. The dysregulated activity of the renin angiotensin aldosterone system (RAAS) is partly responsible for pulmonary edema in COVID-19. ACE2 is known for its effect as the main counter-regulatory mechanism for the renin-angiotensin aldosterone system (RAAS), which is an essential player in blood pressure control by retaining sodium and water and increasing the intravascular fluid volume. SARS-CoV-2 binds ACE2 and accelerates the degradation of ACE2, and thus decreases the counteraction of ACE2 on RAAS. The final effect is increasing reabsorption of sodium and water and subsequent volume overload. The RAAS can be envisioned as a dual function system in which the vasoconstrictor/proliferative or vasodilator/antiproliferative actions are primarily driven by the ACE-ACE2 balance. According to that, an increased ACE/ACE2 activity ratio generated by the downregulation action of SARS-CoV-2 on ACE2 will lead to increased Angiotensin II and increased catabolism of Angiotensin 1-7, towards vasoconstriction, endothelial dysfunction, prothrombosis, proinflammatory, and antinatriuretic effect. Acute pulmonary edema is caused mostly by one of the following mechanisms: pulmonary venous pressure elevation-volume overload-or augmentation of the alveolar capillary membrane permeability-inflammation. In fact, both mechanisms sometimes coexist and the distinction is irrelevant. There are bibliographic references of pulmonary edema in COVID-19, as well as evidence of volume overload in COVID-19: Lang et al. describes frequent and pronounced vasculature in affected lung areas that may be suggestive of disordered vasoregulation. Eslami et al. observed increased cardiothoracic ratio and it is also described as right ventricular dilatation. In this setting, a different approach emerged: moderate or severe COVID-19 could experience a severe acute pulmonary edema with a dual hit. A first hit of pneumonitis-augmentation of the alveolar capillary membrane permeability-can lead to low hydrostatic pressure pulmonary edema. The second hit is high pressure pulmonary edema, caused by increase of hydrostatic pressure secondary to volume overload, a result of dysregulation of the RAAS. This results in a dual hit that triggers severe acute pulmonary edema. If this edema is not solved, then a third hit appears with secondary inflammation, superinfection, fibrosis and finally the typical ARDS. Consequently, the study group looked for patients with pulmonary edema before ARDS was triggered. Cases of moderate and severe COVID-19 were searched, with tomographic evidence of pulmonary edema: dilated superior vena cava, large pulmonary arteries, diffuse interstitial infiltrates and dilated right ventricle. At the detection of pulmonary edema in patients with COVID-19, a standard treatment consisting of oral hydric restriction and diuretics (NEGBAL approach) was initiated. The effects of furosemide on pulmonary edema were well established decades ago. To date there is no evidence that had suggested the model of pulmonary edema and volume overload secondary to the dysregulation of the renin angiotensin aldosterone system in COVID-19. The objective of this study is to compare patients with COVID-19 undergoing NEGBAL approach with a control group of patients with COVID-19 of similar demographic, clinical, gasometric and tomographic characteristics. Medical records of 120 adult patients were reviewed: demographic; clinical, laboratory; Pro b-type natriuretic peptide (pro-BNP): (negative: below 125 pg/mL); high-sensitivity cardiac troponin (hs-cTnT): (negative: <14 ng/L); blood gas; chest tomography (CT); oxygen therapy support and mechanical ventilation (MV) requirements, all of which were reviewed and recorded by investigators. With the purpose of knowing the patient's basal hematocrit before COVID-19, prior hematocrit, if any, defined as hematocrit previous to COVID-19 infection (hematocrit prior to admission to NEGBAL) was also reviewed. Once the NEGBAL strategy began, the clinical, tomographic, gasometric, biochemical evolution was evaluated until the 8th day (until the 12th day for tomography), ICU stay, hospital stay and morbidity and mortality until the 30th day.

Official Title
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Lung Injury (Pulmonary Edema) in COVID-19: Treatment With Furosemide and Negative Fluid Balance (NEGBAL): a Case-Control Study

Conditions
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COVID-19

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Inclusion criteria for patients subjected to NEGBAL group are as follows: confirmed diagnosis of COVID-19 PaO2/FiO2 (ratio of arterial oxygen partial pressure to fractional inspired oxygen) <300; Patients over 18 years of age and tomographic evidence of acute pulmonary edema, defined as dilated superior vena cava, large pulmonary arteries, diffuse interstitial infiltrates with Kerley lines, and dilated right ventricle or dilated cardiac axis. Patients subjected to NEGBAL underwent a treatment with furosemide in continuous intravenous infusion, guided by objectives: Negative Fluid Balance approach (NEGBAL). Inclusion criteria for patients subjected to NO-NEGBAL-Control Group- are as follows: confirmed diagnosis of COVID-19 through real-time reverse transcriptase polymerase chain reaction (RT-PCR) assay with samples obtained from nasopharyngeal swab or positive antinucleocapsid immunoglobulin M (IgM) antibodies; ratio of arterial oxygen partial pressure to fractional inspired oxygen (PaO2/FiO2) <300; age older than 18 years, and tomographic evidence of acute pulmonary edema, defined as dilated superior vena cava, large pulmonary arteries, diffuse interstitial infiltrates with Kerley lines, and dilated right ventricle or dilated cardiac axis. Patients subjected to NO-NEGBAL group, did not receive NEGBAL approach as treatment. Exclusion Criteria for both groups are as follows: patients with prior indication of diuretics for another reason, renal failure, cardiac failure (diagnosis by echocardiography), hepatic failure, hypernatremia or hyponatremia, hypotension or shock.

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 |
| --- | --- |
| NEGBAL<br>Negative Fluid Balance (NEGBAL) Approach: COVID-19 patients with tomographic detection of pulmonary edema (dilated superior vena cava, large pulmonary arteries, diffuse interstitial infiltrates with Kerley lines, and dilated right ventricle or dilated cardiac axis) treated with NEGBAL approach. This consisted of oral hydric restriction and use of diuretics (20 mg of furosemide, intravenous bolus, followed by furosemide in endovenous continuous infusion, starting at 60 mg/day). The objective of this approach was to achieve negative fluid balance, between 600 to 1400 mL/day adjusted to body surface area, with a final target of 8-10% of body weight in up to 8 days. The furosemide dose was titrated considering heart rate and blood pressure, target fluid balance, hematocrit, and serum creatinine. | |
| NO-NEGBAL<br>Treatment for COVID-19 pneumonia in this series were based on standard recommendations. All patients in this group received dexamethasone 6 mg/day and thromboembolic prevention with enoxaparin 40 mg/day. Participants in the NO-NEGBAL group, did not received a NEGBAL approach as treatment. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mortality | Mortality measured in days after admission | Until the 30th day after admission or discharge | 
| Oxygenation | Evolution of oxygenation during hospitalization (measured by PaO2/FiO2). To analyze the correlation between the variation of the PaO2/FiO2 ratio and the NEGBAL variables, a linear regression model of the form PAFIBAL β0+β1NEGBAL was used. For the model, the response variable PAFIBAL was registered as the difference in the PaO2/FiO2 between admission to NEGBAL to day 7. Continuous variables were expressed as means. Categorical variables were summarized as counts. No changes (adjustments) were made for missing data. The paired sample T test was used. All statistical tests were 2-tailed. A p-value < 0.05 was considered statistically significant. The analysis was not adjusted for multiple comparisons and given the possibility of a type I error, the findings should be interpreted as exploratory and descriptive. All analyses were performed using R software, version 4.1.1 (R Foundation for Statistical Computing) | From admission to day 7; until discharge, death, or until the 30th day, depending on which appears first. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with mechanical ventilation requirements (MV invasive) |  | Until discharge, death, or up to 30 days, depending on which appears first. | 
| CT infiltrates | Evaluation of CT infiltrates, measured through the score described by Pan F et al, used as a semiquantitative measurement using the sum of lung involvement-5 lobes. Each lobe on a scale from 0 (normal) to 5 (maximum infiltrate) being the maximum CT score 25. | Prior to starting NEGBAL approach, between admission to day 4, day 8 and day 12 of NEGBAL. | 
| Measurement of the superior vena cava diameter | Measured in CT just above the arch of the azygos veins. Unit of measurement: millimeters (mm) | Prior to starting NEGBAL approach, between admission to day 4, day 8 and day 12 of NEGBAL. | 
| Measurement of cardiac axis diameter | Transverse measurement across the 4 cavities (in centimeters) | Prior to starting NEGBAL approach, between admission to day 4, day 8 and day 12 of NEGBAL. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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furosemide, edema, volume overload, diuretic, NEGBAL - Negative Fluid Balance, COVID-19