Efficacy and Safety of Angiotensin II Use in Coronavirus Disease(COVID)-19 Patients With Acute Respiratory Distress Syndrome

  • STATUS
    Recruiting
  • End date
    Dec 31, 2022
  • participants needed
    50
  • sponsor
    Guy's and St Thomas' NHS Foundation Trust
Updated on 15 August 2021
anakinra
cytokines
respiratory distress
acute respiratory distress
angiotensin
covid-19
norepinephrine
shock
coronavirus
ventilator-induced lung injury
lung injury
coronavirus infection

Summary

This study aims to find out whether the use of angiotensin II, which is a drug to raise blood pressure has been approved by European Medical Agency in August 2019, as an add-on medication to increase blood pressure in patients with COVID-19, acute severe lung injury, inflammation and severe shock, compared with standard medication. In addition, the investigators will collect the data of Anakinra, another drug which is frequently used in this condition to reduce inflammation.

The investigators will collect clinical data and outcomes from critical care patients. The investigators will analyse for whom these drugs are most beneficial and explore whether there are any patients who don't benefit or have side effects.

Description

COVID-19 is a rapidly evolving pandemic with approximately 5% of all patients requiring admission to the intensive care unit. In critically ill patients infected with COVID-19, ARDS is found in 40%, more than 25% require continuous renal replacement therapy, and more than 10% develop vasodilatory shock. Currently, supportive treatment is the mainstay treatment, with fluid administration and vasopressors for haemodynamic support and lung-protective ventilation in patients with severe respiratory failure. Targeted drugs, antiviral therapies, and vaccines are still currently being developed and studied. To date, there is insufficient evidence to recommend any drug over another.

Angiotensin II is a major product of the renin-angiotensin-aldosterone system (RAAS) system. Initially, renin is secreted by hypotension, activation of sympathetic nervous system, and decreased sodium delivery to distal tubules. Renin then stimulates angiotensinogen to be converted into angiotensin I. Angiotensin I is cleaved to angiotensin II by angiotensin-converting enzyme (ACE). ACE is an endothelium-bound ectoenzyme produced by pulmonary endothelium and endothelium from the systemic circulation.

Angiotensin II has a variety of effects, mainly blood pressure elevation via AT-1 receptors, thereby causing direct vasoconstriction, stimulation of vasopressin release for water reabsorption, and stimulation of aldosterone release from the adrenal glands. Angiotensin II is converted to angiotensin(1-7) by angiotensin-converting enzyme 2 (ACE2_. Angiotensin(1-7) has vasodilatory, anti-inflammatory, and anti-apoptotic properties.

The RAAS system may be over- or under-stimulated during sepsis. Diseases that involve pulmonary vasculature e.g. acute respiratory distress syndrome (ARDS) or endotoxaemia can alter ACE function. Studies have shown that patients with lower Ang II and ACE levels were more likely to die. In addition, AT-1 receptors are downregulated from increased inflammatory cytokines, hence diminished vasopressor response in sepsis patients. In COVID-19 patients with ARDS, four mechanisms are proposed in response to deficient functional ACE. First, inadequate production of angiotensin II leads to decreased AT-1 receptor activation, leading to vasodilatation and hypotension. Second, the accumulation of its substrate, angiotensin I, leads to catabolism of angiotensin I into angiotensin(1-7), which causes further vasodilatation. Third, angiotensin(1-7) activates nitric oxide(NO) synthase, stimulates production of NO, another potent vasodilator. Lastly, dysfunctional ACE impairs ACE-dependent hydrolysis of bradykinin, which is another vasodilatory substance. Furthermore, COVID-19 has been shown to bind to the ACE2 receptor for cell entry and viral replication. Angiotensin II has been shown in vitro to downregulate ACE2 by internalization and degradation in both mouse and human models.

Therefore, exogenous angiotensin II is proposed as a potent vasoconstrictor in COVID-19-associated ARDS with vasodilatory shock. Several studies, including a recent randomised controlled trial, have shown angiotensin II as an effective vasopressor. In the largest trial to date, 321 patients were randomized to Ang II (n=163) or placebo (n=158). Most of the included patients had sepsis (80.7%). Patients were included if they were more than 18 years old with vasodilatory shock, defined as mean arterial pressure (MAP) between 55 and 70 mmHg, requiring norepinephrine equivalent dose 0.2 mcg/kg/min for at least 6 hours, had received at least 25 mL/kg crystalloids within the last 24 hours, and met either of the following criteria; cardiac index more than 2.3 L/min, central venous oxygen saturation (ScvO2) > 70%, or central venous pressure (CVP) > 8 mmHg. Patients who were randomized to Ang II had a higher proportion of meeting MAP target of 75 mmHg or a 10 mmHg increase in MAP at 3 hours compared with placebo (69.9% vs 23.4%; p <0.001). Patients who received angiotensin II also had lower noradrenaline requirement at 3 hours and lower cardiovascular SOFA score at 48 hours. Subsequent post-hoc analyses have shown that patients who received Angiotensin II were more likely to be liberated from renal replacement therapy (RRT) within 7 days (38% Ang II versus 15% placebo; p = 0.007). Those who might benefit from Ang II included patients with acute physiologic and chronic health evaluation (APACHE) II score 30, those with elevated renin and lower baseline Ang II levels, and severe ARDS patients with partial pressure of oxygen (PaO2)/fraction of inspired oxygen (FiO2) ratio < 100. In 2019, the European Medical Agency approved angiotensin II as a vasoconstrictor to raise blood pressure in patients with septic or other distributive shock who remain hypotensive despite adequate volume restitution and application of catecholamines and other available vasopressor therapies.

Noradrenaline is currently recommended by the consensus guideline as the first line vasopressor for COVID-19 patients with vasodilatory shock. There is insufficient evidence to issue a treatment recommendation on the use of angiotensin II in critically ill adults with confirmed COVID-19 infection with ARDS and vasodilatory shock. Therefore, this study aims to compare the efficacy of angiotensin II as an add-on vasopressor with optimised standard of care.

Critically ill patients with COVID-19 infection also often receive Anakinra to modulate the inflammatory response. The investigators would also like to collect the data of patients treated with and without Anakinra.

Details
Condition Pulmonary Disease, ADULT RESPIRATORY DISTRESS SYNDROME, Acute Respiratory Distress Syndrome (ARDS), Acute Respiratory Distress, Lung Disease, COVID-19, COVID-19, Coronavirus Disease (COVID-19), COVID-19, COVID-19, Pathogen Infection Covid-19 Infection, *Corona Virus Infection, *COVID-19 Infection, Corona Virus Disease 2019(COVID-19), COVID-19, COVID-19, Treat and Prevent Covid-19 Infection, COVID-19, COVID-19 Infection, *COVID-19, COVID-19, Covid-19, COVID-19, COVID-19 Pneumonia, COVID-19, COVID-19, COVID-19, Covid-19, Pathogen Infection Covid-19 Infection, COVID-19, COVID-19, COVID-19, Use of Stem Cells for COVID-19 Treatment, COVID-19, COVID-19, Hospitalized Patients With Covid-19 Pneumonia, Corona Virus Disease 2019(COVID-19), COVID-19 Pneumonia, COVID-19; Cardiovascular Diseases, Community-acquired Pneumonia, Influenza, COVID-19, Old Age, Usability, Visio Telephony, Confinement, Covid-19, COVID-19 Pneumonia, COVID-19 Pneumonia, Acute Respiratory Distress Syndrome Caused by COVID-19, COVID-19 Pneumonia, Corona Virus Disease 2019(COVID-19), Old Age, Usability, Visio Telephony, Confinement, Covid-19, SARS-CoV-2 (COVID-19) Infection, COVID-19 Pneumonia, Corona Virus Disease 2019(COVID-19), COVID-19 Pneumonia, Severe Coronavirus Disease (COVID-19), Acute Respiratory Distress Syndrome Caused by COVID-19, COVID-19 Pneumonia, COVID-19, Hydroxychloroquine Sulfate, SARS-CoV-2 (COVID-19) Infection, COVID-19 Pneumonia, COVID-19, Hydroxychloroquine Sulfate, Anxiety Related to the COVID-19 Pandemic, Acute Respiratory Distress Syndrome Caused by COVID-19, Severe Coronavirus Disease (COVID-19), COVID-19 Pneumonia, *COVID-19 Infection, Severe Coronavirus Disease (COVID-19), COVID-19 by SARS-CoV-2 Infection, acute respiratory distress syndrome, ards
Treatment Angiotensin II, Interleukin-1 receptor antagonist
Clinical Study IdentifierNCT04408326
SponsorGuy's and St Thomas' NHS Foundation Trust
Last Modified on15 August 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

Adult patients ( 18 years old) admitted to intensive care units overseen by critical care consultants
Confirmed COVID-19 infection
ARDS defined as per the BERLIN ARDS definition1
For angiotensin data only: Vasodilatory shock as diagnosed clinically by the treating physicians and receiving noradrenaline for less than 12 hours from the onset of shock or arrival to hospital

Exclusion Criteria

Pure cardiogenic shock
Stage 4 cancer
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