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.