COVID-19NCT05304702
Lung Injury (Pulmonary Edema) in COVID-19: Treatment With Furosemide and Negative Fluid Balance (NEGBAL)
An observational study of COVID-19, run by Clinica Colon at 1 site in Argentina.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- COVID-19
- Type of treatment
- Pill or oral medicine, Injection or infusion
- How many people
- 120 participants
- Where
- 1 siteArgentina
- Study dates
- 28 Nov 2021to 31 Mar 2022
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Study population: Population of patients with COVID-19 admitted to the ICU in a high complexity healthcare institution of Mar del Plata, Argentina.
Who may be able to join
- 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).
Show all 12Show fewer
- 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.
Who cannot join
- patients with prior indication of diuretics for another reason,
- renal failure,
- cardiac failure (diagnosis by echocardiography),
- hepatic failure,
- hypernatremia or hyponatremia,
- hypotension or shock.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Lung Injury (Pulmonary Edema) in COVID-19: Treatment With Furosemide and Negative Fluid Balance (NEGBAL): a Case-Control Study
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.
Read the detailed description
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.
- Conditions
- COVID-19
- Keywords
- furosemide, edema, volume overload, diuretic, NEGBAL - Negative Fluid Balance, COVID-19
- Medical subject headings
- COVID-19, Edema
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
| Study group | Role | What they receive |
|---|---|---|
| NEGBAL | 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 | 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 being measured
The primary outcome is the main question the study is designed to answer.
Mortality
Mortality measured in days after admission
Measured: 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)
Measured: From admission to day 7; until discharge, death, or until the 30th day, depending on which appears first.
Secondary outcomes (4)
Number of participants with mechanical ventilation requirements (MV invasive)
Measured: 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.
Measured: 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)
Measured: 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)
Measured: Prior to starting NEGBAL approach, between admission to day 4, day 8 and day 12 of NEGBAL.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted31 Mar 2022
- Study start28 Nov 2021
- Primary completion31 Mar 2022
- Study completion31 Mar 2022
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (30)Papers the sponsor has linked to this study.
- Other trials for COVID-19Studies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Case-control
- Time perspective
- Retrospective
- Enrolment
- 120 participants (actual)
Sponsor and investigators
- Lead sponsor
- Clinica Colon
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, José Luis Francisco Santos, Clinica Colon
- Investigators
- José LF Santos, MD, Principal investigator, Clínica Colón - Mar del Plata - Argentina
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05304702
- Sponsor's protocol ID
- UTI-ESI-002
- Status last verified
- Apr 2022
- First submitted
- 17 Mar 2022
- Last updated
- 22 Apr 2022
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided
Publications
Cui X, Chen W, Zhou H, Gong Y, Zhu B, Lv X, Guo H, Duan J, Zhou J, Marcon E, Ma H. Pulmonary Edema in COVID-19 Patients: Mechanisms and Treatment Potential. Front Pharmacol. 2021 Jun 7;12:664349. doi: 10.3389/fphar.2021.664349. eCollection 2021.
PubMed 34163357Xu Z, Shi L, Wang Y, Zhang J, Huang L, Zhang C, Liu S, Zhao P, Liu H, Zhu L, Tai Y, Bai C, Gao T, Song J, Xia P, Dong J, Zhao J, Wang FS. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med. 2020 Apr;8(4):420-422. doi: 10.1016/S2213-2600(20)30076-X. Epub 2020 Feb 18. No abstract available.
PubMed 32085846Rasch S, Schmidle P, Sancak S, Herner A, Huberle C, Schulz D, Mayr U, Schneider J, Spinner CD, Geisler F, Schmid RM, Lahmer T, Huber W. Increased extravascular lung water index (EVLWI) reflects rapid non-cardiogenic oedema and mortality in COVID-19 associated ARDS. Sci Rep. 2021 Jun 1;11(1):11524. doi: 10.1038/s41598-021-91043-3.
PubMed 34075155Kuebler WM, Jordt SE, Liedtke WB. Urgent reconsideration of lung edema as a preventable outcome in COVID-19: inhibition of TRPV4 represents a promising and feasible approach. Am J Physiol Lung Cell Mol Physiol. 2020 Jun 1;318(6):L1239-L1243. doi: 10.1152/ajplung.00161.2020. Epub 2020 May 13.
PubMed 32401673Sun X, Wang T, Cai D, Hu Z, Chen J, Liao H, Zhi L, Wei H, Zhang Z, Qiu Y, Wang J, Wang A. Cytokine storm intervention in the early stages of COVID-19 pneumonia. Cytokine Growth Factor Rev. 2020 Jun;53:38-42. doi: 10.1016/j.cytogfr.2020.04.002. Epub 2020 Apr 25.
PubMed 32360420Mangalmurti N, Hunter CA. Cytokine Storms: Understanding COVID-19. Immunity. 2020 Jul 14;53(1):19-25. doi: 10.1016/j.immuni.2020.06.017. Epub 2020 Jun 28.
PubMed 32610079Langer-Gould A, Smith JB, Gonzales EG, Castillo RD, Figueroa JG, Ramanathan A, Li BH, Gould MK. Early identification of COVID-19 cytokine storm and treatment with anakinra or tocilizumab. Int J Infect Dis. 2020 Oct;99:291-297. doi: 10.1016/j.ijid.2020.07.081. Epub 2020 Aug 6.
PubMed 32768693Hu B, Huang S, Yin L. The cytokine storm and COVID-19. J Med Virol. 2021 Jan;93(1):250-256. doi: 10.1002/jmv.26232. Epub 2020 Sep 30.
PubMed 32592501Fara A, Mitrev Z, Rosalia RA, Assas BM. Cytokine storm and COVID-19: a chronicle of pro-inflammatory cytokines. Open Biol. 2020 Sep;10(9):200160. doi: 10.1098/rsob.200160. Epub 2020 Sep 23.
PubMed 32961074Marini JJ, Gattinoni L. Management of COVID-19 Respiratory Distress. JAMA. 2020 Jun 9;323(22):2329-2330. doi: 10.1001/jama.2020.6825. No abstract available.
PubMed 32329799Sinha P, Matthay MA, Calfee CS. Is a "Cytokine Storm" Relevant to COVID-19? JAMA Intern Med. 2020 Sep 1;180(9):1152-1154. doi: 10.1001/jamainternmed.2020.3313. No abstract available.
PubMed 32602883Gattinoni 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. No abstract available.
PubMed 32228035Kuba K, Imai Y, Rao S, Gao H, Guo F, Guan B, Huan Y, Yang P, Zhang Y, Deng W, Bao L, Zhang B, Liu G, Wang Z, Chappell M, Liu Y, Zheng D, Leibbrandt A, Wada T, Slutsky AS, Liu D, Qin C, Jiang C, Penninger JM. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury. Nat Med. 2005 Aug;11(8):875-9. doi: 10.1038/nm1267. Epub 2005 Jul 10.
PubMed 16007097Imai Y, Kuba K, Rao S, Huan Y, Guo F, Guan B, Yang P, Sarao R, Wada T, Leong-Poi H, Crackower MA, Fukamizu A, Hui CC, Hein L, Uhlig S, Slutsky AS, Jiang C, Penninger JM. Angiotensin-converting enzyme 2 protects from severe acute lung failure. Nature. 2005 Jul 7;436(7047):112-6. doi: 10.1038/nature03712.
PubMed 16001071Liu Y, Yang Y, Zhang C, Huang F, Wang F, Yuan J, Wang Z, Li J, Li J, Feng C, Zhang Z, Wang L, Peng L, Chen L, Qin Y, Zhao D, Tan S, Yin L, Xu J, Zhou C, Jiang C, Liu L. Clinical and biochemical indexes from 2019-nCoV infected patients linked to viral loads and lung injury. Sci China Life Sci. 2020 Mar;63(3):364-374. doi: 10.1007/s11427-020-1643-8. Epub 2020 Feb 9.
PubMed 32048163
Study at a glance
From the registry record, last updated by the sponsor on 22 Apr 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Lung Injury (Pulmonary Edema) in COVID-19: Treatment With Furosemide and Negative Fluid Balance (NEGBAL): a Case-Control Study
- ClinicalTrials.gov ID
- NCT05304702
- Acronym / sponsor ID
- UTI-ESI-002
- Conditions
- COVID-19
- Keywords
- furosemide, edema, volume overload, diuretic, NEGBAL - Negative Fluid Balance, COVID-19
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 120 participants (actual)
- Lead sponsor
- Clinica ColonUniversity, hospital or other
- Study start
- 28 Nov 2021 (actual)
- Primary completion
- 31 Mar 2022 (actual)
- Study completion
- 31 Mar 2022 (actual)
- First posted
- 31 Mar 2022 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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
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.
Study design
- Observational model
- Case-control
- Time perspective
- Retrospective
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| NEGBAL | – | –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 | – | –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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
- Study population
- Population of patients with COVID-19 admitted to the ICU in a high complexity healthcare institution of Mar del Plata, Argentina.
Key inclusion criteria (12 listed)
- 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).
Key exclusion criteria (6 listed)
- patients with prior indication of diuretics for another reason,
- renal failure,
- cardiac failure (diagnosis by echocardiography),
- hepatic failure,
- hypernatremia or hyponatremia,
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
Mortality
Time frame: Until the 30th day after admission or discharge
Mortality measured in days after admission
Oxygenation
Time frame: From admission to day 7; until discharge, death, or until the 30th day, depending on which appears first.
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)
4 secondary outcomes
Number of participants with mechanical ventilation requirements (MV invasive)
Time frame: Until discharge, death, or up to 30 days, depending on which appears first.
CT infiltrates
Time frame: Prior to starting NEGBAL approach, between admission to day 4, day 8 and day 12 of NEGBAL.
Measurement of the superior vena cava diameter
Time frame: Prior to starting NEGBAL approach, between admission to day 4, day 8 and day 12 of NEGBAL.
Measurement of cardiac axis diameter
Time frame: Prior to starting NEGBAL approach, between admission to day 4, day 8 and day 12 of NEGBAL.
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 22 Apr 2022.
- Background: PubMed 34163357Cui X, Chen W, Zhou H, Gong Y, Zhu B, Lv X, Guo H, Duan J, Zhou J, Marcon E, Ma H. Pulmonary Edema in COVID-19 Patients: Mechanisms and Treatment Potential. Front Pharmacol. 2021 Jun 7;12:664349. doi: 10.3389/fphar.2021.664349. eCollection 2021.
- Background: PubMed 32085846Xu Z, Shi L, Wang Y, Zhang J, Huang L, Zhang C, Liu S, Zhao P, Liu H, Zhu L, Tai Y, Bai C, Gao T, Song J, Xia P, Dong J, Zhao J, Wang FS. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med. 2020 Apr;8(4):420-422. doi: 10.1016/S2213-2600(20)30076-X. Epub 2020 Feb 18. No abstract available.
- Background: PubMed 34075155Rasch S, Schmidle P, Sancak S, Herner A, Huberle C, Schulz D, Mayr U, Schneider J, Spinner CD, Geisler F, Schmid RM, Lahmer T, Huber W. Increased extravascular lung water index (EVLWI) reflects rapid non-cardiogenic oedema and mortality in COVID-19 associated ARDS. Sci Rep. 2021 Jun 1;11(1):11524. doi: 10.1038/s41598-021-91043-3.
- Background: PubMed 32401673Kuebler WM, Jordt SE, Liedtke WB. Urgent reconsideration of lung edema as a preventable outcome in COVID-19: inhibition of TRPV4 represents a promising and feasible approach. Am J Physiol Lung Cell Mol Physiol. 2020 Jun 1;318(6):L1239-L1243. doi: 10.1152/ajplung.00161.2020. Epub 2020 May 13.
- Background: PubMed 32360420Sun X, Wang T, Cai D, Hu Z, Chen J, Liao H, Zhi L, Wei H, Zhang Z, Qiu Y, Wang J, Wang A. Cytokine storm intervention in the early stages of COVID-19 pneumonia. Cytokine Growth Factor Rev. 2020 Jun;53:38-42. doi: 10.1016/j.cytogfr.2020.04.002. Epub 2020 Apr 25.
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- Individual participant dataSharing planned: Undecided
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
José LF Santos, MD principal investigator
Clínica Colón - Mar del Plata - Argentina
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of COVID-19, run by Clinica Colon at 1 site in Argentina.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 12 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 22 Apr 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Argentina. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Mortality (time frame: Until the 30th day after admission or discharge). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT05304702, which also lists 30 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 22 Apr 2022.