Angiotensin II and COVID-19
As we learn more about the pathophysiology of COVID-19, alternative treatments are being explored for the severe sequelae of this disease. SARS-CoV-2 enters human cells via the ACE2 receptor, located in many organs, including the heart, vascular endothelium, and alveolar epithelium causing an inflammatory cascade that can lead to ARDS, vasodilatory shock, myocarditis, acute kidney injury and capillary leak. ACE2 also plays a vital role in the renin-angiotensin-aldosterone-system (RAAS), converting angiotensin II into other physiologically active peptides with anti-inflammatory and hypertensive effects. As reported in the ATHOS-III trial, angiotensin II has been utilized in refractory distributive shock. Given the relationship between SARS-CoV-2 and the RAAS, is there a role for angiotensin II in vasodilatory shock caused by COVID-19?
Angiotensin II (ANGII) is an endogenous peptide that increases blood pressure through a variety of mechanisms. It is produced from the precursor, angiotensinogen, that is produced in the liver and cleaved to angiotensin I by renin. Renin is made by the kidneys and excreted when the juxtaglomerular apparatus senses a decrease in renal perfusion. Angiotensin I is then converted to ANGII by angiotensin converting enzyme (ACE). ANGII subsequently is acted upon by ACE2, leading to other downstream effects. ANGII acts primarily on two receptors, AT1R and AT2R.
AT1R are located on vascular smooth muscle, endothelium, heart, brain, kidney, adrenal gland, and adipose tissue, facilitating most of the physiological functions induced by ANG II. Studies of AT2R reveal that the effects of signaling pathways through activation of this receptor may oppose those effects of AT1R, leading to more vasodilatory effects, although the mechanism is still being elucidated. ANGII increases blood pressure via vasoconstriction of the peripheral vasculature, enhancement of ADH and adrenocorticotropic hormones, activation of sympathetic nerve fibers, and contraction of vascular smooth muscle.
Patients with severe ARDS secondary to COVID-19 may have dysfunctional ACE from cytotoxic damage to the pulmonary endothelium and ensuing inflammation. This may prevent conversion of angiotensin I to angiotensin II, increasing a patient’s likelihood of succumbing to distributive shock from lack of vasoconstriction, sympathetic activation, and reduced renal sodium and water retention.
A case report describing the use of angiotensin II in COVID-related illness was recently published in April 2020 that describes an elderly woman with acute hypoxemic respiratory failure from COVID. She developed refractory hypoxemia despite lung protective mechanical ventilatory support per ARDSnet protocol and prone ventilation,. Forty eight hours after admission, she progressed to renal and hepatic failure with subsequent vasodilatory shock requiring norepinephrine and vasopressin further complicated by acute cardiomyopathy. Despite appropriate resuscitation, her vasopressor requirement continued to rise, concerning for catecholamine-resistant shock. Angiotensin II infusion was initiated resulting in rapid hemodynamic improvement. She was weaned off norepinephrine and vasopression while remaining on angiotensin II infusion for 8 days. Ultimately, she tolerated discontinuation of angiotensin II and remained hemodynamically stable. While this single case report does not establish angiotensin II as the first-line vasopressor for distributive shock in severe COVID-19, it certainly calls for further study.
Critical care teams continue to battle COVID-19, utilizing dynamic and evolving strategies for hemodynamic and ventilatory support. Angiotensin II may be efficacious and beneficial in patients with COVID-related refractory vasodilatory shock given the underlying pathophysiology of the disease process coupled with lessons learned from the ATHOS-III trial.
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