NO-mediated Vascular Function in Covid-19 Patient

COVID-19 Pneumonia Clinical Trial

Official title:

Pilot Study on Peripheral Vascular Function in Covid-19 Patient

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04625036
• Other study ID #: ICS Maugeri 2437 CE
• Status: Completed
• Start date: May 30, 2020
• Est. completion date: May 10, 2021

Study information

• Verified date: April 2022
• Source: Istituti Clinici Scientifici Maugeri SpA
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational [Patient Registry]

Clinical Trial Summary

The 2019 coronavirus-induced infection (COVID-19) has caused a pandemic that has spread worldwide. Up to date, many subjects affected by the virus report important sequelae on different organs increasing morbidity and exacerbating previous pathological conditions. Mortality is also increased in cases of comorbidities such as cardiovascular disease, hypertension and diabetes. COVID-19 infection is caused by Coronavirus-2 (SARS-CoV-2). Concerning the specific interaction of SARS-CoV-2 with the cardiovascular system, we know that this virus enters the body through the receptors for the conversion of angiotensin II (ACE2r) that are present in the lungs, heart, intestinal epithelium and vascular endothelium. This receptor's availability suggests a multi-organ involvement with a consequent multi-organ dysfunction, as found in patients affected by SARS-CoV-2 infection. Furthermore, poor vascular peripheral function -usually correlated with old age and long periods of bed rest or hypomobility- is a distinguishing characteristic of the population affected by COVID-19, as well. Thus, it is reasonable to expect that peripheral vascular function, already deteriorated by aging and common age-related diseases, can be further compromised by COVID-19 and by the forced hypomobility, typically experienced during the acute phase of the disease. The main aim of this project will be to investigate the peripheral NO-mediated vascular function in the leg of patients recovering from Covid-19 pneumonia. A significant vascular dysfunction is expected to be found in post COVID individuals and to be correlated to the relevant clinical variables.

Description:

The 2019 coronavirus-induced infection (COVID-19) has caused a pandemic that has spread worldwide, causing approximately 250,000 deaths to date. Even if the contagion curves seem to stabilize, many subjects have been affected by the virus and report important sequelae on the cardiovascular system. This can be explained by the assumption that COVID-19 interacts with the cardiovascular system at different levels, increasing morbidity and exacerbating previous pathological conditions. Mortality is, in fact, increased in cases of comorbidities such as cardiovascular disease, hypertension and diabetes. COVID-19 infection is caused by Coronavirus-2 (SARS-CoV-2). This virus enters the body through the receptor for the conversion of angiotensin [angiotensin-converting enzyme 2, ACE2]. This receptor is present in the lungs, heart, intestinal epithelium and vascular endothelium. The receptor's availability suggests a multi-organ dysfunction, as found in patients affected by SARS-CoV-2 infection. In particular, the infection of endothelial cells or pericytes, as well as the cytokine-mediated inflammatory cascade induced by the infection, can lead to severe microvascular and macrovascular dysfunctions. It is important to underline that endothelial damage is one of the precursors of the atherosclerosis and endothelial dysfunction is related to pulmonary, cardiac and neurological diseases. Furthermore, poor vascular function is related to old age and long periods of bed rest or hypomobility, those characteristics are present in the population affected by COVID-19, as well. Thus, it is reasonable to expect that peripheral vascular function, already deteriorated by aging and common age-related diseases, can be further compromised by COVID-19 and by the forced hypomobility typically experienced during the acute phase of the disease. Recently, the endothelial function mediated by nitric oxide (NO) has been easily and non-invasively investigated on common femoral artery with the ultrasound technique of Single Passive Leg Movement. The main aim of this project will be to investigate the NO-mediated vascular function in patients recovering from Covid-19 pneumonia, within one month from discharge in order to verify the presence of endothelial dysfunction acutely induced by the viral infection. The secondary aim will be to evaluate the correlation between NO-mediated vascular function (evaluated by ultrasound technique) and age, anthropometric parameters (height, weight, Body Mass Index), clinical parameters, oxygenation status, physical performance and pharmacology. The data will be analysed with the Shapiro-Wilk test to evaluate their "normality" and will be presented as mean ± standard deviation (sd) or median (interquartile range) depending on the type of distribution detected. Correlation tests (Pearson/Spearman) between ultrasound evaluation on peripheral blood flow and vessels and oxygenation levels, clinical, anthropometric and physical performance measures will then be performed. Values of p <0.05 will be considered significant. A significant peripheral vascular dysfunction is expected to be found in post COVID individuals and to be correlated to relevant clinical variables (i.e. muscle strength, respiratory parameters, oxygenation status).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 22
• Est. completion date: May 10, 2021
• Est. primary completion date: April 30, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 30 Years to 80 Years

Eligibility

Inclusion criteria:

• Diagnosis of COVID-19 pneumonia
• Clinical stability condition (temperature <37.5 ° C, Respiratory Rate (RR) <22 breaths/min, Heart Rate (HR)> 50 beats/minute and <120 beats/minute, absence of major arrhythmias, hemodynamic stability)
• Possibility to reach the sitting position independently Exclusion criteria: -Previous cardiovascular, respiratory, neurological or orthopaedic diseases.

Related Conditions & MeSH terms

• COVID-19
• COVID-19 Pneumonia

Intervention

Diagnostic Test:
• Single passive leg movement
The investigation consists of a non-invasive evaluation by ultrasounds performed on the common femoral artery investigating the speed of arterial blood flow [Leg Blood Flow LBF] and diameter of vessel with a dedicated ultrasound system (General Electric Medical Systems, Milwaukee, WI) using Doppler method, before and after a passive flexion-extension movement of the knee. A linear probe will be used with a frequency of 5 MHz. Using the diameter of the artery and the average volume (Vmean), the LBF will be calculated every second with the formula=Average volume*PiGreco*(vessel diameter / 2)2*60. The subject will be placed in a sitting position for 20 minutes before the test. The protocol consists of image acquisition for 60 seconds (basal measurement), followed by a passive flexion-extension of the knee (single passive leg movement). The knee flexion will be performed by health care personnel at a rate of 1 Hz. At the end of the movement, the recording will continue for 60 seconds.

Locations

Country	Name	City	State
Italy	ICS Maugeri IRCCS, U.O. Emergenza Coronavirus di Lumezzane	Lumezzane	Brescia

Sponsors (2)

Lead Sponsor	Collaborator
Istituti Clinici Scientifici Maugeri SpA	Universita di Verona

Country where clinical trial is conducted

Italy, 

References & Publications (10)

Andrews AW, Thomas MW, Bohannon RW. Normative values for isometric muscle force measurements obtained with hand-held dynamometers. Phys Ther. 1996 Mar;76(3):248-59. — View Citation

Broxterman RM, Trinity JD, Gifford JR, Kwon OS, Kithas AC, Hydren JR, Nelson AD, Morgan DE, Jessop JE, Bledsoe AD, Richardson RS. Single passive leg movement assessment of vascular function: contribution of nitric oxide. J Appl Physiol (1985). 2017 Dec 1;123(6):1468-1476. doi: 10.1152/japplphysiol.00533.2017. Epub 2017 Aug 31. — View Citation

Casanova C, Celli BR, Barria P, Casas A, Cote C, de Torres JP, Jardim J, Lopez MV, Marin JM, Montes de Oca M, Pinto-Plata V, Aguirre-Jaime A; Six Minute Walk Distance Project (ALAT). The 6-min walk distance in healthy subjects: reference standards from seven countries. Eur Respir J. 2011 Jan;37(1):150-6. doi: 10.1183/09031936.00194909. Epub 2010 Jun 4. — View Citation

Gifford JR, Richardson RS. CORP: Ultrasound assessment of vascular function with the passive leg movement technique. J Appl Physiol (1985). 2017 Dec 1;123(6):1708-1720. doi: 10.1152/japplphysiol.00557.2017. Epub 2017 Sep 7. Review. — View Citation

Guzik TJ, Mohiddin SA, Dimarco A, Patel V, Savvatis K, Marelli-Berg FM, Madhur MS, Tomaszewski M, Maffia P, D'Acquisto F, Nicklin SA, Marian AJ, Nosalski R, Murray EC, Guzik B, Berry C, Touyz RM, Kreutz R, Wang DW, Bhella D, Sagliocco O, Crea F, Thomson EC, McInnes IB. COVID-19 and the cardiovascular system: implications for risk assessment, diagnosis, and treatment options. Cardiovasc Res. 2020 Aug 1;116(10):1666-1687. doi: 10.1093/cvr/cvaa106. — View Citation

Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, Schiergens TS, Herrler G, Wu NH, Nitsche A, Müller MA, Drosten C, Pöhlmann S. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell. 2020 Apr 16;181(2):271-280.e8. doi: 10.1016/j.cell.2020.02.052. Epub 2020 Mar 5. — View Citation

Paneroni M, Pasini E, Vitacca M, Scalvini S, Comini L, Pedrinolla A, Venturelli M. Altered Vascular Endothelium-Dependent Responsiveness in Frail Elderly Patients Recovering from COVID-19 Pneumonia: Preliminary Evidence. J Clin Med. 2021 Jun 9;10(12). pii — View Citation

Strassmann A, Steurer-Stey C, Lana KD, Zoller M, Turk AJ, Suter P, Puhan MA. Population-based reference values for the 1-min sit-to-stand test. Int J Public Health. 2013 Dec;58(6):949-53. doi: 10.1007/s00038-013-0504-z. Epub 2013 Aug 24. — View Citation

Trinity JD, Groot HJ, Layec G, Rossman MJ, Ives SJ, Runnels S, Gmelch B, Bledsoe A, Richardson RS. Nitric oxide and passive limb movement: a new approach to assess vascular function. J Physiol. 2012 Mar 15;590(6):1413-25. doi: 10.1113/jphysiol.2011.224741. Epub 2012 Feb 6. — View Citation

Venturelli M, Layec G, Trinity J, Hart CR, Broxterman RM, Richardson RS. Single passive leg movement-induced hyperemia: a simple vascular function assessment without a chronotropic response. J Appl Physiol (1985). 2017 Jan 1;122(1):28-37. doi: 10.1152/japplphysiol.00806.2016. Epub 2016 Nov 10. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Leg Blood Flow	Leg Blood Flow will be analyzed with an ultrasound examination using the Single Passive Leg Movement technique.; In particular, the investigation consists of an ultrasound performed on the common femoral artery using Doppler method with a linear probe with a frequency of 5 MHz.; The subject will be placed in a sitting position at rest for 20 minutes before the test is performed. The protocol consists of image acquisition for 60 seconds (basal measurement), followed by a passive flexion-extension of the knee performed by health care personnel at a rate of 1 Hz. At the end of the movement, the recording will continue for another 60 seconds.	Baseline
Secondary	Clinical evaluations	Routinary measures as single anthropometric data: height (cm) and weight (Kg) and aggregate measure as body mass index (Kg/m2)	Baseline
Secondary	Clinical characteristics	Clinical course of disease (days) will be noted for all subjects	Baseline
Secondary	Presence of device	Ventilatory support (yes or no) will be noted for all subjects	Baseline
Secondary	Therapy	Drug therapy (list of drugs) will be noted for all subjects	Baseline
Secondary	Clinical characteristics	Number of comorbidities will be noted for all subjects	Baseline
Secondary	Biochemical evaluations - ProBNP	All subjects will perform blood tests to investigate bio-humoral data. Normal values: <125 pg/mL	Baseline
Secondary	Biochemical evaluations - D-dimer	All subjects will perform blood tests to investigate bio-humoral data. Normal values:<500 ng/mL FEU	Baseline
Secondary	Biochemical evaluations - PCR	All subjects will perform blood tests to investigate bio-humoral data. Normal values:<=5.00 mg/L	Baseline
Secondary	Functional evaluations - 1-Minute Sit To Stand	Therapists ask the participants to sit down on a chair without armrests. The assisted use of the arms is not allowed during the STS test. The therapists instruct the participants to complete as many sit-to-stand cycles as possible within 60 s at self-paced speed and count the number of fully-completed STS cycles. Normal values: 50/min-27/min.	Baseline
Secondary	Functional evaluations - 6-Minute Walking Test	The 6MWT is a self-paced test of walking capacity. Patients will be asked to walk as far as possible in 6 min along a flat corridor. The distance in metres is recorded. Standardised instructions and encouragement are given during the test.; Predicted 6MW Distance follows this calculation: 361-(age in yrs x 4) + (height in cm x 2) + (HRmax/HRmax % pred x 3) - (weight in kg x 1.5) - 30 (if females).	Baseline
Secondary	Functional evaluations - Biceps' muscle strength with dynamometer	The patient will be seated with the elbow flexed 90" and forearm supinated; the dynamometer will be positioned just proximal to styloid processes and the patient will be asked to flex his elbow. Prediction equation=229.421-84.836*(0=male, 1=female) +0,165*weight-1.503*age.	Baseline
Secondary	Functional evaluations - Quadriceps' muscle strength with dynamometer	The patients will be seated with hips and knees flexed 90''; the dynamometer will be positioned just proximal to malleoli and the patient will be asked to extend his knee. Prediction equation=358.455-87.581*(0=male, 1=female) +0.297*weight-3.136*age	Baseline