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

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.